Why does HPV Infect Squamous Epithelial Cells and Not Others?

Why does HPV Infect Squamous Epithelial Cells and Not Others?

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I've seen this question about HPV and the reference therein. The link states "Human papillomavirus (HPV) is a DNA virus that presents tropism for epithelial cells, causing infections of the skin and mucous membranes. Replication of HPV occurs in the nuclei of squamous cells and its life cycle is directly related to the differentiation program of the host cell. "

Why does HPV infect squamous epithelial cells and not others, what are the major differences? And why can't that difference be used to provide medication?

The answer usually lies in whether the cell of interest expresses the correct receptor.

Check this:

This excerpt from that review explains why:

"Although both the α6β4 and α6β1 heterodimer were capable of binding VLPs in vitro, only the former was supposed to function as a HPV receptor, which was concluded from the results that the α6 subunit associated preferentially with the β4 in epithelial cells [12], and the α6β4 complex was expressed exclusively in the basal cellular layer of the stratified squamous epithelium [13], which was presumably the only site of productive PV infection"

Koilocytosis or koilocytic atypia or koilocytotic atypia are terms used in histology and cytology to describe the presence of koilocytes in a specimen. [1]

Koilocytes may have the following cellular changes:

    enlargement (two to three times normal size).
  • Irregularity of the nuclear membrane contour, creating a wrinkled or raisinoid appearance.
  • A darker than normal staining pattern in the nucleus, known as hyperchromasia.
  • A clear area around the nucleus, known as a perinuclear halo or perinuclear cytoplasmic vacuolization. [2]

Collectively, these types of changes are called a cytopathic effect various types of cytopathic effect can be seen in many different cell types infected by many different viruses. [2] Infection of cells with HPV causes the specific cytopathic effects seen in koilocytes.

The atypical features seen in cells displaying koilocytosis result from the action of the E5 and E6 oncoproteins produced by HPV. These proteins break down keratin in HPV-infected cells, resulting in the perinuclear halo and nuclear enlargement typical of koilocytes. [3] The E6 oncoprotein, along with E7, is also responsible for the dysregulation of the cell cycle that results in squamous cell dysplasia. The E6 and E7 oncoproteins do this by binding and inhibiting the tumor suppressor genes p53 and RB, respectively. This promotes progression of cells through the cell cycle without appropriate repair of DNA damage, resulting in dysplasia. [4] Due to the ability of HPV to cause cellular dysplasia, koilocytes are found in a number of potentially precancerous lesions.

Koilocytes can be visualized microscopically when tissue is collected, fixed, and stained. Though koilocytes can be found in lesions in a number of locations, cervical cytology samples, commonly known as Pap smears, frequently contain koilocytes. [5] In order to visualize koilocytes collected from the cervix, the tissue is stained with the Papanicolaou stain. [5] Another way koilocytes can be visualized is by fixation of tissue with formalin and staining with hematoxylin and eosin, commonly known as H&E. [5] These stains give the cytoplasm and nuclei of cells characteristic colors and allows for visualization of the nuclear enlargement and irregularity, hyperchromasia, and perinuclear halo that are typical of koilocytes.

Koilocytes may be found in potentially precancerous cervical, oral and anal lesions.

Cervical lesions Edit

Atypical Squamous Cells of Undetermined Significance (ASC-US) Edit

When examining cytologic specimens, a diagnosis of ASC-US is given if squamous cells are suspicious for Low-Grade Squamous Intraepithelial Lesion (LSIL) but do not fulfill the criteria. This may be due to limitations in the quality of the specimen, or because the abnormalities in the cells are milder than that seen in LSIL. [6] Cells in this category display koilocyte-like changes such as vacuolization, but not enough changes to definitively diagnose as LSIL. [6] A diagnosis of ASC-US warrants further follow-up to better characterize the extent of the abnormal cells. [4]

Low-Grade Squamous Intraepithelial Lesion (LSIL) Edit

In LSIL of the cervix, definitive koilocytes are present. In addition, squamous cells commonly display binucleation and mitoses are present, signifying increased cellular division. [7] However, these changes are primarily limited to upper cell layers in the epithelium, no mitoses are found higher than the lower one third of epithelium, and the basal layer of cells remains a discrete layer. This differentiates this lesion from High-Grade Squamous Intraepithelial Lesion (HSIL) of the cervix. [7]

Oral lesions Edit

Verruca Vulgaris Edit

Verruca vulgaris, or common warts, may arise in the oral mucosa. These lesions are associated with HPV subtypes 1, 6, 11, and 57. [8] Histopathology of these lesions displays koilocytes in the epithelium. [8]

Oropharyngeal cancer Edit

Approximately 50 percent of oropharyngeal cancers are associated with HPV infection. [4] Koilocytosis is the most common cytopathic effect present in HPV-related oropharyngeal cancers. [9] However, the current standard of care for these tumors includes verification of HPV status using methodologies other than the histopathologic presence or absence of koilocytes alone. [10] These methodologies include polymerase chain reaction (PCR), in situ hybridization (ISH), and immunohistochemistry (IHC). [10]

Anal lesions Edit

Anal intraepithelial neoplasia Edit

Histopathologic changes seen in LSIL of the cervix can also be seen in anal epithelium. Koilocytes are characteristic of LSIL in the anus. In contrast to LSIL, HSIL in the anus consists of abnormal basaloid cells replacing more than half of the anal epithelium. [11]

These changes occur in the presence of human papillomavirus and occasionally can lead to cervical intraepithelial neoplasia, and if left untreated some may eventually progress to malignant cancer.

  1. ^ ab Nucci MR, Oliva E, eds. (2009). Gynecologic pathology: A volume in the series - Foundations in diagnostic Pathology. Elsevier Churchill Livingstone. ISBN978-0-443-06920-8 .
  2. ^ ab
  3. DeMay, Richard M. (2007). Practical Principles of Cytopathology Revised. American Society for Clinical Pathology. ISBN978-0-89189-549-7 .
  4. ^
  5. Shurin, Michael R. Thanavala, Yasmin Ismail, Nahed, eds. (2015). Infection and Cancer: Bi-Directorial Interactions. Springer. doi:10.1007/978-3-319-20669-1. ISBN978-3-319-20669-1 . Retrieved 12 November 2020 .
  6. ^ abc
  7. Klatt, Edward C. Kumar, Vinay (2010), "The Female Genital Tract", Robbins and Cotran Review of Pathology, Elsevier, pp. v, ISBN978-1-4160-4930-2 , retrieved 2020-11-12
  8. ^ abc Krause, Katherine A. Neelon, Daniel Butler, Samantha L. (2020), "Koilocytosis", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30422553, retrieved 2020-11-23
  9. ^ ab
  10. Gynecologic and obstetric pathology. Volume 2. Zheng, Wenxin., Fadare, Oluwole., Quick, Charles Matthew., Shen, Danhua., Guo, Donghui. Singapore: Springer. 2019. ISBN978-981-13-3019-3 . OCLC1108535716. CS1 maint: others (link)
  11. ^ ab
  12. Molavi, Diana Weedman. The practice of surgical pathology : a beginner's guide to the diagnostic process (Second ed.). Cham, Switzerland. ISBN978-3-319-59211-4 . OCLC1002923571.
  13. ^ ab Porter, Stephen Leão, Jair C. Gueiros, Luiz Alcino (2019), "Oral and Maxillofacial Viral Infections", Contemporary Oral Medicine, Cham: Springer International Publishing, pp. 983–1007, 978-3-319-72301-3, retrieved 2020-11-11
  14. ^ Miyahara, Glauco Issamu Simonato, Luciana Estevam Mattar, Neivio José Camilo Jr, Deolino João Biasoli, Eder Ricardo (2011). "Correlation between koilocytes and human papillomavirus detection by PCR in oral and oropharynx squamous cell carcinoma biopsies". Memórias do Instituto Oswaldo Cruz. 106 (2): 166–169. doi:10.1590/S0074-02762011000200008. ISSN 0074-0276.
  15. ^ ab van Zante, Annemieke Jordan, Richard C. (2020), "Detection Methods for Human Papillomavirus (HPV) in Head and Neck Cancers", Textbook of Oral Cancer, Cham: Springer International Publishing, pp. 119–125, 978-3-030-32315-8, retrieved 2020-11-11
  16. ^ Lightner, Amy L. Kin, Cindy J. Welton, Mark L. (2018-12-25), "Anal Intraepitheial Neoplasia", Fundamentals of Anorectal Surgery, Cham: Springer International Publishing, pp. 347–357, 978-3-319-65965-7, retrieved 2020-11-12

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Path to improved health

Your Pap test will come back with one of three results:

Normal (or negative). This means no cell changes were found.

Unclear (or inconclusive). This result is common. It means it looks like your cells could be abnormal. This could be because of an infection, such as a yeast infection or the herpes virus. Hormone changes from pregnancy or menopause can also affect test results.

Abnormal (or positive). This means cell changes were found. In most cases, it does not mean you have cervical cancer. There are different abnormal test results. These are the most common.

  • ASC-US – Atypical squamous cells of undetermined significance
    This is the most common abnormal finding. It is sometimes considered an unclear result rather than abnormal. Squamous cells form the surface of your cervix. This result means the squamous cells don’t look normal. This could be because of an infection, including HPV.
  • AGC – Atypical glandular cells
    Glandular cells produce mucus in your cervix and uterus. This result means some glandular cells don’t look normal. These cell changes are usually more serious than ASC (atypical squamous cells). This means there is a greater risk that precancer or cancer is present.
  • LSIL – Low-grade squamous intraepithelial lesions
    This result is sometimes called mild dysplasia. It indicates low-grade changes that are usually caused by an HPV infection. Changes may go away on their own.
  • HSIL – High-grade squamous intraepithelial lesions
    This result is also called moderate or severe dysplasia. It indicates that HPV is present and is causing more serious changes. These could turn into cancer if left untreated.
  • ASC-H – Atypical squamous cells, cannot exclude HSIL
    Some cells are not normal, and there is a possibility that HSIL is also present.
  • AIS – Adenocarcinoma in situ
    An advanced lesion was found in the glandular tissue. It could turn into cancer if left untreated.
  • Cervical cancer cells (squamous cell carcinoma or adenocarcinoma)
    Pap tests can detect cancer cells, but it is rare. Cancer usually does not have time to develop in women who get regular cancer screenings.

Most women with abnormal cervical cancer screening results do not have cancer.

If your screening found ASC-US, your doctor will probably order an HPV test. He or she may also have you come back in 6 to 12 months for another Pap test. If the HPV test is positive and you are older than 25, your doctor will order a colposcopy. During this test, he or she will use a magnifying lens to look more closely at your cervix. They can also take a sample of tissue (biopsy) to test for cancer.

Cells of the cervix go through many changes before they turn into cancer. A Pap test can show if your cells are going through these changes. If caught and treated early, cervical cancer is not life threatening. Talk to your doctor to see how often he or she recommends you receive Pap tests. You may need them or less often, depending on your age and overall health.


HPV infection is initially asymptomatic 10 and transmission between people occurs before overt expression of the virus is seen or felt. Clinically, HPV infects the basal cells of the epithelium 11 of skin and mucous membranes. 12 Because HPV may affect sites where there are epithelial cells, 13 infections have been documented in the oral mucosa, oesophagus, larynx, trachea, conjunctiva, 14 as well as genital and anal areas. 12 HPV has not been identified in gastrointestinal mucosa. 15

Infection may present in various ways. Latent HPV may be asymptomatic identified only by molecular biology techniques, or subclinical, seen on colposcopy. 14 The virus may present as hyperplastic, hyperkeratotic warts or dysplastic lesions that may undergo neoplastic transformation. 14

Non-genital warts may be passed on by fomites or direct contact with even a small area of broken skin. 12 Alternatively, genital warts are passed on through direct contact with the lesion. 12 Genital warts in females appear initially on the posterior introitus and adjacent labia the warts then spread to the vulva, and eventually to the vagina and cervix. 12 Genital warts can cause intense discomfort with associated pruritis, bleeding, and secondary infection caused by superficial injury due to scratching. 12

Perhaps more important than the initial wart lesions that recur over the years, are the consequences of the latent infection with this virus—that is, dysplasia, neoplasia, and cervical cancer that occurs in a significant portion of these women. Important questions to ask include: Why do some women carry HPV for years with minimal sequelae while others are afflicted with carcinoma in situ? How can we prevent the spread of this potentially fatal virus? What is the role of the Papanicolaou (PAP) smear in the prevention of the more detrimental outcomes of this virus?

Myths about the HPV virus:

Quite the opposite. It&rsquos actually really common, so common in fact that four in every five people (80%) will have the virus at some point in their lives. This is why clueing ourselves up on the virus is so important.

2. HPV is something to worry about

There are over 100 types of HPV and the majority are nothing to worry about. There are, however, at least 13 high risk types that can cause cancer. That's can, not will. In most cases, if you or any partners get high-risk HPV your bodies will be able to clear the infection, just like it does with any low risk infections. In a few cases the infection can cause abnormalities in the cells of the cervix which, if not detected and monitored, may develop in to cervical cancer. This is why it is important to attend your smear tests when invited, so that any abnormal cells can be caught before they get the chance to develop into cancer.

3. You will know if you have HPV

False. HPV normally has no signs or symptoms so it is very difficult to tell if someone has it. By attending your regular smear tests, high-risk HPV infection and any abnormalities caused by the infection can be identified and treated if needed.

4. Only promiscuous people get HPV

You can get HPV the very first time you have sexual contact, so this is really not true. HPV is passed on through skin to skin contact of the genital area, so if you have had several sexual partners, or one of your partners has, you simply have a higher chance of having come into contact with the virus. But because it's really common, you can be infected even if you have only ever had one partner. The HPV virus can also lie inactive inside the body for up to 20 years, so if you have a long term partner and find out you have HPV this is not an indication that they have been unfaithful!

5. HPV is a young person&rsquos virus

Nope. HPV is passed by skin to skin contact of the genital area so anyone who has ever been sexually active can have HPV. It is more common in young, sexually active people, however, the immune system will usually clear the infection so this isn&rsquot really something to worry about. It's important to remember that HPV can remain dormant for long periods of time, so even if you have been with the same partner for many years or have not been sexually active for a long time, you can still have the virus. That's why it's important to keep attending your smear tests regularly throughout your life, until you are no longer invited.

6. You won&rsquot get HPV if you&rsquore healthy

HPV infections are very common so while having a healthy lifestyle can help your body to protect itself from HPV, the only way to entirely avoid having the virus is abstinence. Yeah, probably not a popular option for most people&hellip..

So where does being healthy come in? Your immune system is responsible for fighting off HPV infection, so the healthier it is the more effectively it can do its job. Eating well, exercising, and, most importantly, not taking up or stopping smoking can all help. However, HPV can affect anyone who is sexually active, even very healthy people, so you can&rsquot fully reduce your chance of getting it no matter how many green juices you drink and yoga classes you go to.

7. HPV doesn&rsquot affect LGBT+ people

It&rsquos a common myth that HPV only affects straight people &ndash in fact according to the LGBT Foundation, 17.8% of lesbian, gay and bisexual (LGB) women of eligible screening age have never been for cervical screening. If you&rsquove ever had sexual contact of any kind, then you are at risk of getting HPV. This includes oral sex and anal sex, not just penis-in-vagina sex. It&rsquos less common, but HPV can also be transmitted via sharing sex toys, or through any kind of intimate touching. HPV doesn&rsquot discriminate &ndash regardless of your gender identity or sexual orientation, you might pick it up along the way.

8. If you use a condom you won&rsquot get HPV

Not true, sadly. Wearing condoms will reduce your risk of getting the virus, but because HPV can live on the skin in and around the whole genital area, it won't all be covered by a condom. HPV can therefore be transmitted through sexual contact of any kind including any touching or genital to genital contact, as well as oral, vaginal and anal sex.

9. There&rsquos no relationship between smoking and HPV infection

Smoking is actually a major risk factor for developing cervical cancer. If you smoke, your immune system around the cells of the cervix may be weakened, making it harder for the body to prevent and clear high-risk HPV infections which could cause abnormal cells to develop.

10. The HPV vaccine means you won&rsquot get HPV

If you have had the HPV vaccination you are protected against at least 70% of cancer causing HPV strains, but you're absolutely not fully protected. Attending smear tests is just as important if you have been vaccinated or not as it will detect abnormalities caused by other types of HPV.

While it's true that HPV causes cervical cancer which is a woman&rsquos disease, it can also lead to penile, anal, and head and neck cancers (among others). All genders have a head and a neck, so both male and females should be protected by vaccination from HPV and should remember to be aware of the effects of infection.

12. If you have HPV you will probably get cancer

It is true that 99.7% of all cervical cancers are caused by HPV, but that doesn't mean that 99.7% of people with HPV will get cancer. Far from it most people will have HPV without any problem. In order to protect yourself you should make sure you attend your smear tests when invited, get the HPV vaccination if you're eligible, and make sure you know the signs and symptoms of cervical cancer. And don't forget to visit your GP if you are concerned.

Over 3,000 women are diagnosed with cervical cancer each year, but if more women understand the steps they can take to reduce their risk, one day it could be a disease of the past. Watch this video to learn more:

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Whereas the development of AIDS related malignancies such as Kaposi's sarcoma and non-Hodgkin's lymphoma are attributable to immune deficiency, the relation between HIV and cervical cancer is more complex. Some authors have commented on the lack of a significant difference regarding the severity of neoplasia in asymptomatic HIV positive women and those with AIDS.

Cervical cancer has long been associated with HPV infection. Undermining of the cell cycle checkpoints through the actions of the E6 and E7 proteins interacting with p53 and pRb, respectively, is well known. 6 However, this alone is insufficient to cause cervical cancer, and other carcinogens and further genetic changes are required for disease progression.

Pathways of tumour progression

Two pathways of tumorigenesis have been postulated. The first is the loss of tumour suppressor genes, referred to as the loss of heterozygosity (LOH) pathway, and the other involves genetic instability at the microsatellite loci. This instability is believed to arise as a result of defects in the mismatch repair (MMR) genes, making them unable to repair slippage errors that occur during replication. However, loss of cell cycle checkpoints could also cause this instability. Lazo reviewed the studies conducted on this and states that of 344 cases, only 28 display microsatellite instability (MSI) (8%). 35 Thus, in cervical cancer, the loss of tumour suppressor genes seems to be the usual pathway of progression. LOH has also consistently been detected at specific loci such as 3p14.1–p22, 4p16, 6p21, 3p25, and 17p13.3. 36– 38 This has led to rampant speculation as to candidate tumour suppressor genes. An increased rate of MSI has been described in several HIV related malignancies including Kaposi's sarcoma, non-Hodgkin's lymphoma, anal intraepithelial neoplasia, and HIV associated lung cancers. 39 A significantly higher frequency of MSI has also been observed in HIV related CIN lesions, and these changes were found to be independent of CD4 counts. 40 Similar HPV subtypes were found in both HIV positive and sporadic CIN lesions, and there was no difference in the frequency of high risk HPV positive and high risk HPV negative CIN lesions. Thus, these changes appear to be independent of HPV type and HIV induced immune suppression. In addition, the pathogenesis of the increasing incidence and more aggressive behaviour of cervical lesions in HIV positive patients seem to be mirrored by a different tumour pathway.

There are several possible explanations. It has been suggested that HIV may target the MMR genes or other repair pathways. Alternatively, a viral protein may specifically bind to the DNA or cellular proteins, corrupting the replication process. However, the HIV genome has not been detected in cervical tumour samples and, in those studies where it has been detected in low copy numbers, it has been attributed to HIV in background inflammatory cells. The hypothesis that HIV might use a “hit and run” mechanism, modifying the cell without detection of the viral genome, should also be considered. 41 Graham et al postulated that the pathway of tumour progression is determined by a specific cell cycle checkpoint aberration. 42 Loss of control at the G1/S checkpoint allows the accumulation of numerous small genetic changes, leading to microsatellite instability, with unchecked progression through G2/M allowing loss of larger segments of DNA code, and thus causing LOH.

To account for this difference in both clinical and molecular behaviour, there are several schools of thought, each implicating different biological aspects. As mentioned, some favour HIV targeting of specific genes. Others have suggested local immune dysregulation involving both alteration in cervical cell profile and alteration of cytokine profiles. Aberration of systemic immunity has also been implicated, whereas some favour direct viral–viral interactions.

Have HPV? How to clear the infection naturally

Q&A with Dr. Manny: My OB-GYN recently told me I have HPV. Because I'm over the age limit for the vaccine, is there anything else I can do to help get rid of it?

The human papillomavirus, or HPV, is the most common sexually transmitted infection (STI) in the United States. In fact, it's so common that nearly all sexually active men and women get it at some point in their lives.

There are over 100 different kinds of HPV, but only some of them can cause serious health problems like genital warts or cancer of the cervix, vagina, vulva or anus.

We got this question from a viewer:

Dear Dr. Manny,
My OB-GYN recently told me I have HPV. I know it's extremely common and that your immune system can naturally clear the infection over time, but I'm still freaking out about it. Because I'm over the age limit for the vaccine, is there anything else I can do to help get rid of it?

Testing positive for HPV does not automatically mean you will get cancer. Some studies estimate that 50 percent of those infected with HPV will clear the virus within eight months— and 90 percent will be cured within two years. It's only when your immune system isn’t able to fight off the infection that some strains of HPV can persist and possibly lead to cancer.

Getting regular screenings and pap tests are important for early detection in women. The Food and Drug Administration (FDA) has approved an HPV test for women over 30 years old, but there is currently no HPV test for men.

“If a woman has HPV, there is an increased risk of transmission to her partner,” Dr. Jennifer Landa, an OBGYN and Chief Medical Officer of BodyLogicMD, told “Many partners will never develop any problems, but there is an increasing incidence of oral cancers in men that seem to be transmitted from oral sex with HPV-positive partners.”

Men and women can lower their risk of HPV by getting vaccinated. The FDA has approved three HPV vaccines for use in the U.S., and research has shown they are highly effective against certain strains of HPV that cause health problems like genital warts and cancer. The Centers for Disease and Prevention (CDC) recommends all boys and girls ages 11 or 12 years should get vaccinated. Because the vaccines work only before you get infected, experts say it’s better for kids to get vaccinated before becoming sexually active.

There is no cure for the HPV virus, but there are several things you can do to help your body clear the virus, and lower your chances of it persisting and turning into cancer.

“You want to do a few things,” Landa said. “First, avoid smoking, and if you smoke, quit smoking. Second, avoid oral contraceptives. Studies show that the birth control pill can increase your likelihood of HPV turning into cancer.”

Women with HPV need to decide with their doctor if they want to stop taking the pill and should finish their current pack before planning for their next method of birth control if they want to protect against pregnancy, Landa suggested.

Birth control in the form of an intrauterine device (IUD) also comes with a warning, Landa said.

“You want to consider using the copper IUD rather than the one that contains hormones. The hormone containing IUD was just shown in a study to reduce clearance of HPV,” she said.

As your immune system is the first line of defense against HPV, boosting it can help fight off the virus naturally.

“I would tank up on certain vitamins,” Landa said. “Several vitamins have been shown to increase the likelihood of clearing the HPV.”

“The first one is B vitamins— especially Folic acid and B12. I would recommend Folic Acid 1000mcg— [the] best form is methyltetrahydrofolate (MTHF). And For B12, I would recommend at least 1000mcg per day in the form of methylcobalamin.”

Landa also suggested taking certain forms of vitamin E.

“I would recommend 400iu, comprised of mixed tocopherols including beta and gamma tocopherols. Most of the vitamin E sold is delta tocopherol, so you want to make sure you're getting a vitamin E with "mixed tocopherols" that includes the beta and gamma forms to get the results you're looking for.”

What is HPV?

HPV is short for human papillomavirus. HPVs are a group of more than 150 related viruses. Each HPV virus is given a number, which is called an HPV type. HPVs are called papillomaviruses because some HPV types cause papillomas (warts), which are non-cancerous tumors. But some types of HPV are known to cause cancer, including cancers of the cervix (the base of the womb at the top of the vagina), vagina, vulva (the area around the outside of the vagina), penis, anus, and parts of the mouth and throat.

HPVs are attracted to and can live only in certain cells called squamous epithelial cells. These cells are found on the surface of the skin and on moist surfaces (called mucosal surfaces) like:

  • The vagina, cervix, vulva (area around the outside of the vagina), and anus
  • The inner foreskin and urethra of the penis
  • The inner lining of the nose, mouth, and throat
  • The trachea (windpipe) and bronchi (smaller breathing tubes branching off the trachea)
  • The inner eyelids

Cutaneous (skin) HPV types

Most HPV types are called cutaneous because they cause warts on the skin, such as on the arms, chest, hands, and feet. These are common warts, not genital warts.

Mucosal (genital) HPV types

The other HPV types are considered mucosal types because they invade and live in cells on mucosal surfaces. The mucosal HPV types are also called genital (or anogenital) HPV types because they often affect the anal and genital area. These types can also infect the lining of the mouth and throat. Mucosal HPV types generally don’t grow in the skin or parts of the body other than the mucosal surfaces.

Low-risk mucosal (genital) HPV types: HPV types that tend to cause warts and rarely cause cancer are called low-risk types. Low-risk genital HPV infection can cause cauliflower-shaped warts on or around the genitals and anus of both men and women. In women, warts may appear in areas that aren’t always noticed, such as the cervix and vagina.

High-risk mucosal (genital) HPV types: HPV types that can cause cancer are called high-risk types. These types have been linked to certain cancers in both men and women. Doctors worry about the cell changes and pre-cancers these types cause because they are more likely to grow into cancers over time.

This diagram shows the different groups of HPV types and the problems each group can cause.

Case 38

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1 . Question

Anal pap of a 34 year old male

  • A. Normal Cytology
  • B. Low-grade squamous intraepithelial lesion
  • C. High-grade squamous intraepithelial lesion
  • D. Atypical squamous cells

Answer: B. Low-grade squamous intraepithelial lesion

Low-grade squamous intraepithelial lesions (LSIL), also referred to as anal intraepithelial neoplasia 1 (AIN1), is a manifestation of human papillomavirus (HPV) infection. The cells of anal LSIL typically have eosinophilic or orangeophilic cytoplasm with enlarged round to oval nuclei, greater than two times the size of an intermediate nucleus. Nuclei are hyperchromatic with granular chromatin and irregular nuclear membranes. In anal LSIL smears, typical koilocytes are less frequently seen than in cervical smears. In anal smears, it is important to the presence or absence of the anal transition zone, which lies between the colorectal columnar epithelium and squamous epithelium and is represented by columnar, cuboidal, or polygonal glandular cells.

It is important to distinguish LSIL from non-HPV-related changes. On anal smears, it is essential to rule out reactive epithelial changes associated with infection, such as herpes simplex infection. Care should especially be taken in HIV-positive patients, who are prone to multiple infectious diseases, to avoid a misdiagnosis of malignancy.

Figures A and C: Typical changes of LSIL in an anal smear. Cells are binucleate with nuclear enlargement, nuclear membrane irregularities, condensation of the cytoplasm, and a perinuclear halo.

Figure B: Glandular cells of the anal transition zone.

Bibbo M and Wilbur DC. Comprehensive Cytopathology, 4th ed. Elsevier Saunders, 2015.

Answer: B. Low-grade squamous intraepithelial lesion

Low-grade squamous intraepithelial lesions (LSIL), also referred to as anal intraepithelial neoplasia 1 (AIN1), is a manifestation of human papillomavirus (HPV) infection. The cells of anal LSIL typically have eosinophilic or orangeophilic cytoplasm with enlarged round to oval nuclei, greater than two times the size of an intermediate nucleus. Nuclei are hyperchromatic with granular chromatin and irregular nuclear membranes. In anal LSIL smears, typical koilocytes are less frequently seen than in cervical smears. In anal smears, it is important to the presence or absence of the anal transition zone, which lies between the colorectal columnar epithelium and squamous epithelium and is represented by columnar, cuboidal, or polygonal glandular cells.

It is important to distinguish LSIL from non-HPV-related changes. On anal smears, it is essential to rule out reactive epithelial changes associated with infection, such as herpes simplex infection. Care should especially be taken in HIV-positive patients, who are prone to multiple infectious diseases, to avoid a misdiagnosis of malignancy.

Figures A and C: Typical changes of LSIL in an anal smear. Cells are binucleate with nuclear enlargement, nuclear membrane irregularities, condensation of the cytoplasm, and a perinuclear halo.

Figure B: Glandular cells of the anal transition zone.

Bibbo M and Wilbur DC. Comprehensive Cytopathology, 4th ed. Elsevier Saunders, 2015.

HPV-Associated Cancers and Precancers

Persistent infection with oncogenic types of HPV has a causal role in nearly all cervical cancers and in many vulvar, vaginal, penile, anal, and oropharyngeal cancers (789). However, the only HPV-associated cancer for which routine screening is recommended is cervical cancer.

Cervical Cancer

Screening Recommendations

Recommendations for cervical cancer screening in the United States are based on systematic evidence reviews and are largely consistent across the major medical organizations, including ACS, ACOG, and USPSTF (124-126) ( Routine cervical screening should be performed starting at age 21 years and continue through age 65 years to prevent invasive cervical cancer. Testing can be performed using either conventional or liquid-based cytologic tests (i.e., Pap tests). For women aged &ge30 years, screening can include several FDA-approved oncogenic or high risk HPV (HR-HPV) tests. For cytopathologic and HR-HPV testing, clinics should use CLIA-certified laboratories using acceptable terminology (Bethesda 2001 or LAST terminology) (790,791). Annual cervical cancer screening is no longer recommended for all women. Instead, Pap testing is recommended every 3 years from ages 21&ndash29 years. During age 30&ndash65 years, women should either receive a Pap test every 3 years or a Pap test plus HPV test (co-test) every 5 years co-testing can be done by either collecting one swab for the Pap test and another for the HPV test or by using the remaining liquid cytology material for the HPV test. Because of the high negative predictive value of two tests, women who test negative for both HPV and Pap test should not be screened again for 5 years. Cervical screening programs should screen women who have received HPV vaccination in the same manner as unvaccinated women. All major medical organizations concur that no Pap testing is recommended before age 21 years.

Women should be given a copy of their test results (Pap and HPV, if applicable) those with normal results should also be provided with general recommendations regarding when to schedule follow-up visits and the importance of cervical cancer screening. Women with abnormal screening tests should be referred to providers who are experienced in managing these cases (see Follow-Up). Women should be reassured and counseled about abnormal cervical cancer screening test results and informed about any implications for sex partner(s). (See counseling messages for HPV infection and for women receiving cervical cancer screening.)

The following additional management considerations are associated with performing Pap tests:

  • The Pap test should not be considered a screening test for STDs.
  • All women should receive cervical cancer screening, regardless of sexual orientation (i.e., women who identify as lesbian, bisexual, or heterosexual).
  • Ideally, women should be advised to have a Pap test 10&ndash20 days after the first day of menses. However, this test can be performed during menstruation depending on menstrual flow and type of cytology used (liquid-based cytology can differentiate cells from blood and mucus conventional Pap test might not).
  • If specific infections other than HPV (e.g., chlamydia or gonorrhea) are identified at the visit, the woman might need to have a repeat Pap test after appropriate treatment for those infections. However, in most instances (even in the presence of some severe infections), Pap tests will be reported as satisfactory for evaluation, and reliable final reports can be produced without the need to repeat the Pap test after treatment is received.
  • The presence of a mucopurulent discharge should not postpone Pap testing. The test can be performed after removal of the discharge with a saline-soaked cotton swab.
  • In the presence of cervical friability (see Cervicitis), liquid-based cytology should be used conventional pap testing might need to be deferred in the presence of heavy bleeding until cervicitis is treated.
  • In the absence of other indications, women who have external genital warts do not need Pap tests more frequently than women who do not have warts.
  • The sequence of Pap testing in relation to collection of other endocervical specimens does not influence Pap test results or their interpretation (792). In general, vaginal specimens are preferred for chlamydia and gonorrhea screening in women, but in the setting of a pelvic exam, endocervical specimens for STD testing can be collected first.
  • Women who have had a total hysterectomy do not require a routine Pap test unless the hysterectomy was performed because of cervical cancer or its precursor lesions. In women whose cervix remains intact after a hysterectomy, regularly scheduled Pap tests should be performed as indicated (793-795).
  • Health-care facilities that train providers on Pap test collection and employ simple quality assurance measures are more likely to obtain satisfactory test results (as determined by the laboratory).
  • The use of instruments designed to sample to the cervical transformation zone (e.g., cytobrushes) improves the accuracy of Pap tests (796).
  • Liquid-based cytology is an acceptable alternative to conventional Pap tests, as it has similar test-performance characteristics.
  • At an initial visit, providers should ask women about their most recent Pap test and results and history of evaluation and treatment (e.g., loop electrosurgical excision procedure and colposcopy) to assist with management every effort should be made to obtain copies of recent results. The importance and frequency of Pap testing or co-testing (Pap and HPV testing) should be reinforced.

HPV Tests for Cervical Cancer Screening

Clinical tests for oncogenic types of HPV are used for 1) cervical cancer screening in conjunction with a Pap test, 2) triage of abnormal cervical cytology results, and 3) follow-up after treatment of cervical precancers. These tests are only approved for use with cervical specimens, not oral or anal specimens. The role of testing for non-oncogenic HPV types (e.g., 6 and 11) is unclear and is not recommended.

Current FDA-cleared HPV tests detect viral nucleic acid (DNA) or messenger RNA (mRNA). Several FDA-cleared tests for HPV are available for use in the United States, but use of non-oncogenic (e.g., types 6 and 11) tests is not recommended (110). The Hybrid Capture 2 High-Risk HPV DNA test (Qiagen, Gaithersburg, Maryland) and the Cervista HPV High-Risk DNA test (Hologics, Beford, Massachusetts) detect presence of 13&ndash14 oncogenic HPV types, whereas the Cervista HPV 16/18 DNA test only detects oncogenic HPV types 16 and 18. The Digene HC2 HPV DNA test (Qiagen, Gaithersburg, Maryland) detects 13 oncogenic or five non-oncogenic HPV types. The Cobas 4500 (Roche, Pleasanton California) test detects 14 oncogenic HPV DNA types and can detect individual types HPV 16 and 18, while the APTIMA HR HPV (Gen Probe, San Diego CA) test detects 14 oncogenic HPV types of HPV mRNA. Aptima HPV 16/18/45 test is also FDA-cleared to triage its pooled Aptima HR HPV test further, although there are no algorithms for HPV 16/18/45 testing in any clinical guidelines. HPV assays should be FDA-cleared and used only for the appropriate indications (110).

In the United States, HPV tests to detect oncogenic types of HPV infection are most commonly used to triage Pap test results indicating atypical squamous cells of undetermined significance (ASC-US) in women aged &ge25 years (110). HPV testing for oncogenic types are now being incorporated into cervical cancer screening recommendations with Pap tests (i.e., co-testing) to reduce follow-up visits in women aged >30 years (see Screening Recommendations). HPV testing can be performed on the same swab as used for the Pap test or a separate supplied swab reflex testing of residual material of a liquid-based cytology specimen is another option. HPV testing for 16 and 18 is also used to triage discordant test results (i.e., in the case of a negative Pap test and positive HPV test). In the future, oncogenic (high-risk) HPV tests might be considered for primary cervical cancer screening, but no such recommendation has been made by any medical organization.

HPV testing (including oncogenic HPV and HPV 16/18 tests) should not be performed in the following situations:

  • Deciding whether to vaccinate against HPV
  • Conducting STD screening in women or men at risk for STDs
  • Providing care to persons with genital warts or their partners
  • Conducting screening for cervical cancer as a stand-alone test (i.e., without a concurrent Pap test)
  • Testing women aged <30 years as part of routine cervical cancer screening or
  • Testing oral or anal specimens.


If the results of the Pap test are abnormal, follow-up care should be provided according to ASCCP 2012 Consensus Guidelines for Management of Abnormal Cervical Cytology (110). If clinic resources do not allow for follow-up of women with abnormal results, protocols for linkage to follow-up care and management should be in place. The following are highlights of the ASCCP guidelines.

  • Women aged 21&ndash24 years are managed more conservatively than other women because of potential harms of overtreatment and low risk for cancer. For women in this age group who have ASC-US or LSIL, cytology should be repeated in 12 months.
  • For women with ASC-US cytology, either cytology can be repeated in 12 months (for women of all ages) or reflex HPV testing can be performed (for women aged &ge25 years).
  • For women with ASC-US who are HPV negative, a repeat HPV and Pap test in 3 years is recommended.
  • For women who have normal cytology but lack endocervical cells, a repeat Pap is not required. For women who have unsatisfactory cytology, regardless of negative HPV result, a repeat cytology is required in 2&ndash4 months.
  • HPV 16/18 testing is one follow-up option for women who have discordant results (normal Pap test accompanied by a positive HPV test). If the HPV 16/18 test is positive, women should immediately receive colposcopy. If negative, these women should repeat the HPV co-test in 1 year.
  • For women with LSIL or HSIL, management should be provided by a specialist according to existing guidelines ( external icon ).

Clinics in settings serving women who might not adhere to follow-up recommendations for whom linkage to care is unlikely should consider offering in-house colposcopy and biopsy services. ASCCP has an app available for purchase and download for management of abnormal cytologic and histologic results. Although this app takes current results into consideration, clinicians are required to have knowledge of past abnormal Pap or cervical procedures to provide management guidance (


Women might believe the Pap test screens for conditions other than cervical cancer or might be confused by abnormal results (797-799). Health-care providers, a trusted source of information about HPV and abnormal Pap test results, are critical in educating women about high-risk HPV and can moderate the psychosocial impact of abnormal results (1,735,800,801). Women should be counseled on the risks, uncertainties, and benefits of screening (126,802). Education, counseling, and follow-up reminders by phone, text, or email might increase screening and adherence to follow-up (803). Multiple forms of communication (e.g., in-person counseling and printed or online information) might be more effective than one form alone (804). Print materials and online resources are available at .

Abnormal Pap test and/or HPV test results can cause short-term anxiety, stress, fear, and confusion, decreasing women&rsquos ability to absorb and retain information and possibly acting as a barrier to follow-up care (798,805-807). A positive HPV test might exacerbate these feelings and elicit concerns about partner(s) worry about disclosure and feelings of guilt, anger, and stigmatization (800,806). Providers should frame oncogenic HPV positivity in a neutral, nonstigmatizing context and emphasize its common, asymptomatic, and transient nature. Providers also should emphasize that HPV is often shared between partners. Therefore, having HPV does not imply infidelity, nor should it raise concerns about a partner&rsquos health (800).

Key Messages for Women Regarding Cervical Cancer Screening
  • Cervical cancer can be prevented with regular screening tests, like the Pap test and the HPV DNA test (HPV test). All women should start getting regular Pap tests at age 21 years.
  • The Pap test can find abnormal cells on a woman&rsquos cervix, which could lead to cervical cancer over time, and an HPV test detects HPV infection of the cervix. The HPV test can be used at the same time as the Pap test (known as &ldquoco-testing&rdquo) for women aged &ge30 years. The HPV test also can be used after an inconclusive Pap test among women aged &ge25 years testing for this purpose is known as &ldquoreflex HPV testing.&rdquo
  • Positive Pap and HPV tests are markers of early signs of cervical cancer, which often does not cause symptoms until it is advanced. Appropriate follow-up is essential to ensure that cervical cancer does not develop. All women, even those who feel healthy, should receive screening for cervical cancer.
  • HPV is a common infection and is often cleared from the body without any medical interventions. A positive HPV test does not mean that a person has cancer.
  • HPV is often shared between partners and can lie dormant for many years having HPV does not imply infidelity, nor should it necessarily raise concerns about a partner&rsquos health (

Management of Sex Partners

The benefit of disclosing a positive oncogenic HPV test to current and future sex partners is unclear. The following counseling messages can be communicated to sex partners:

  • Sex partners do not need to be tested for HPV.
  • Sex partners tend to share HPV, even though signs of HPV such as an abnormal Pap-test result might occur in only one partner. Sex partners of persons with HPV infection also likely have HPV.
  • When used correctly and consistently, condoms might lower the risk for HPV infection and might decrease the time to clear in women with HPV infection. However, HPV can infect areas not covered by the condom and might not fully protect against HPV.

Additional messages for partners include the messages for persons with HPV (see Counseling Messages for Persons with HPV).

Special Considerations


Pregnant women should be screened at the same intervals as nonpregnant women. However, pregnant women with abnormal screening tests should be referred to a specialist (808-810), because treatment recommendations differ for this population. A swab, Ayre&rsquos spatula, or cytobrush can be used for obtaining Pap tests in pregnant women (811-813).


The prevalence of the diverse genotypes of HPV seen in our cohort is similar to other Italian and European populations [14]. HPV 16 has been confirmed as the prevalent genotype in CIN2+ and is generally, by itself, responsible for the pathology (single genotype) [15].

In the absence of viral infection, the risk of relapse is minimal. On the other hand, the cone with negative margins in the presence of persistent HPV 16 infection has a high incidence of relapse and thus persistent infection with HPV 16 should be considered a risk factor for the development of CIN2+ relapse.

HPV vaccination for HPV 16 type may be useful in preventing recurrence of CIN 2/3 and CIS.

There are some limitations in our study that include the small sample size, the retrospective design and the limited long-term follow-up. However, follow-up is still underway.

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