Cervical disease and cervical cancer affect women in the United States and across the globe. Cervical cancer develops in the cervix, where the vaginal canal and uterus meet. It is unique among cancers in that it is usually caused by infection with a virus, the human papillomavirus (HPV). At one time, cervical cancer was the leading cause of cancer death for women in the United States.¹ The increased use of Pap testing for cervical disease detection beginning in the 1950s contributed to a dramatic decline in invasive cervical cancer rates.² With proper screening and the development of an HPV vaccine, cervical cancer is now a highly preventable disease.³ In this article, you will learn about:

• The origin and history of cervical cancer
• How cervical cancer develops from human papillomavirus (HPV)
• The two distinct types of cervical cancer
• The symptoms, stages, and signs of cervical cancer and HPV infection
• Screening guidelines for cervical cancer
• Types of cervical cancer tests
• Groups most at risk for cervical cancer
• HPV vaccinations
• Ways to help prevent cervical cancer

With greater awareness about cervical cancer, healthcare providers and patients can work together to prevent it.

Hologic: A Leader in Cervical Disease Screening

Hologic, Inc., is a global healthcare and diagnostics company that develops technology and products that help patients live healthier lives. The Hologic Diagnostic Solutions division strives to make advances toward greater certainty for customers through cutting-edge technology. As part of our Women’s Health portfolio, we offer assays that detect the activity and presence of high-risk HPV infection in women. Our HPV tests and liquid-based cytology tests help healthcare providers identify patients at high risk for cervical disease that can lead to cervical cancer. Pap and HPV screening are recommended in differing combinations and frequencies for the detection of cervical disease for women dependent upon their ages and level of risk.⁴ HPV and Pap testing, along with HPV vaccinations, can help healthcare providers prevent, detect and treat cervical disease and cancer early.⁴

The Discovery and Origins of HPV and Cervical Cancer

Cervical cancer was one of several types of cancers first recorded by the Greek doctor Hippocrates.⁵ As early as 1834, scientists began to suspect that a sexually transmitted disease might be responsible for cervical cancer, in part because the cancer was found more commonly in married women than nuns.^6,7 In 1928, Dr. George Nicholas Papanicolaou was the first scientist to record discernible differences in the cytopathology – or cell characteristics – of cancerous and non-cancerous cells from a patients’ cervices.⁸ Dr. Papanicolaou smeared cells on microscopic slides to examine them and noticed these differences. This process was named after Dr. Papanicolaou and developed into what we know now as the “Pap smear.”⁸ Papillomaviruses have existed in animals for millions of years, targeting different areas of the body, including feet and skin from various parts of the body.⁹ Genital warts, which are caused by HPV, were recorded by ancient Greeks and Romans and mentioned in a number of texts in the years following.¹⁰ The first recording of the infectiousness of genital warts occurred in the 1920s.¹⁰ In the 1970s, further research showed that different types of HPV existed and were associated with different types of warts on the body (i.e., the hands, feet and genitals).¹⁰ In 1972, scientists hypothesized that HPV may be a cause of cervical cancer.¹⁰ They hypothesized this because of the high number of medical reports of rare genital warts that developed into cancer.¹⁰ Until then, much research had been done to investigate herpes simplex virus (HSV) as a cause of cervical cancer and failed to find it was a cause.¹⁰ The scientist Harald zur Hausen discovered that HPV led to cervical cancer.¹¹ For this discovery, he was later awarded the Nobel Prize.¹¹ In 1996, a new type of Pap test was FDA approved: Liquid-based Pap testing.¹² In 2003, the first high-risk HPV assay (molecular test) was approved by FDA.¹³

The State of Cervical Cancer Today

Today, cervical cancer rates are in a much better place than they were as few as 40 years ago, thanks to the development of the Pap smear, liquid-based Pap testing and HPV testing.

In the United States

Cervical cancer rates declined by more than 60% between 1955 and 1992 in the US.¹⁴ Prior to the Pap smear, cervical cancer was one of the most common cancers and causes of death among women in the US. and globally.¹⁴ Today, it is the 14^th most common cancer in the US.¹⁴ In the US. in 2017, the American Cancer Society estimates that approximately 12,820 new cases of invasive cervical cancer will be diagnosed, and 4,210 women will die.² Improvements in cervical cancer treatment have been made, increasing the 5-year survival rate for women with cervical cancer to 75%.¹⁴

Worldwide

The World Health Organization estimates more than 1 million women globally live with cervical cancer.¹⁵ Unfortunately, cervical cancer disproportionately affects developing countries, due to a lack of resources and healthcare and a slower uptake of modern cervical cancer screening.¹⁵ Approximately 84% of cervical cancer cases and 85% of cervical cancer related deaths occur in the developing world.¹⁶

Prevalence of HPV

HPV is so common that nearly all sexually active men and women get it at some point in their lives.¹⁷ Most cases of infection – 90% globally – clear within 2 years of infection.¹⁶ In the small percentage of cases in which HPV persists, it can cause cervical cancer and other problems.¹⁶ In 2015, an estimated 12,990 new cases of cervical cancer occurred in the US. alone.¹⁸ Globally that same year, 270,000 deaths occurred from cervical cancer.¹⁸ In developing countries where effective screening is limited, cervical disease is often not identified until it has advanced to develop symptoms.¹⁶

What are HPV and Cervical Disease?

Human papillomavirus, commonly known as HPV, is the most common sexually transmitted infection in the US.¹⁷ There are more than 150 different strains of HPV, and most people are infected with at least one strain in their lifetimes.¹⁹ In the large majority of HPV infections, the virus goes away on its own without consequence.¹⁹ In some cases, however, HPV can lead to serious consequences. Of 40 types of HPV that affect the genital tract, at least 14  types of HPV are “high risk” and can cause cervical cancer, while others can cause genital warts.²⁰ Because there is no existing cure for HPV infection, it is important that we understand the virus.²¹ Since Harald zur Hausen discovered the connection between HPV and cervical cancer, we have learned much about how the virus develops into disease and cancer.

Symptoms and Signs of Cervical Cancer

The large majority of HPV infections have no symptoms at all.¹⁷ When symptoms do happen, the various types of HPV may present in different ways.¹⁷ The most common symptom or sign of HPV is genital warts.¹⁷ These may appear in or around the vagina, anus, penis or scrotum.¹⁷ They may appear flat or raised and may or may not be a different color than surrounding skin.¹⁷ If a woman has HPV that has developed into cervical precancer or cancer, she may notice symptoms including abnormal or heavy periods, spotting between periods, abdominal pain, pain during sex, or unusual vaginal discharge.²² The path in which cervical cancer develops consists of four basic steps: HPV transmission, viral persistence, progression of infected cells to precancer and finally, invasion.⁹ HPV is a transient viral infection, so these steps can work backwards, as well, to clear infection or cell change from precancer back to normal cells.⁹

Transmission

HPV is so common that nearly all men and women get it at some point in their lives.¹⁷ Approximately 90% of all HPV infections clear within 2 years of initial infection.¹⁶ HPV is transmitted through vaginal, anal and oral sex.¹⁷ It can be passed from a man to a woman, from a woman to a man, from a woman to a woman or from a man to a man.¹⁷ HPV can be transmitted even with the regular use of condoms, because the virus can live on parts of the skin that are not covered by a condom.¹⁷ Most people will have an HPV infection at some point during their lives, though most will have no idea that they are infected and have no symptoms.¹⁷ Testing is not recommended or available for men, so it is impossible to know if they are infected unless they develop certain cancers.¹⁷ If you are a man and concerned that you may have contracted HPV, speak with your healthcare provider about your options.

Persistence

Of the 150 types of HPV, types 16, 18 and 45, are responsible for 80% of cervical cancer. ²³ When these HPV types are present in cervical tissue, they sometimes persist in spite of a person’s immune system warding them off.²⁴

Progression and Cervical Cancer Stages

When the virus persists, it can cause cells to develop microscopic changes at a cellular level.⁹ The virus actually becomes a part of the human’s genome and causes it to act differently than normal.⁹ Change to cervical tissue is called cervical intraepithelial neoplasia (CIN), and is diagnosed through a cervical biopsy.²⁴ CIN is classified as mild (CIN 1), moderate (CIN 2) or high-grade (CIN 3). Moderate and high-grade changes are commonly called precancer. The percentage of CIN3 lesions that progress to invasive cervical cancer has been estimated to be 50% or less.²⁴

Invasion

Left untreated, abnormal cells can spread deeper into tissues, developing into cervical cancer.⁹ There are many more cervical precancers than cancers, which suggests that only a small percent of precancer develops into cancer.⁹

Types of Cancer and Other Consequences of HPV

Squamous Cell Carcinoma and Adenocarcinoma

It can take decades for cervical cancer to develop in a healthy woman with a normal immune system.¹⁶ In women with HIV infection or who otherwise have weakened immune systems, cervical cancer can develop more quickly.¹⁶ Cervical cancer typically develops as one of two types: squamous cell carcinomas (90% of cervical cancers) and adenocarcinomas (most of the remaining 10% of cervical cancers).²⁵ The type of cancer present will determine the path of treatment.

Genital Warts

As mentioned, some types of HPV can cause genital warts. Among these cases, 90% are caused from HPV types 6 and 11.²⁴ In some cases, warts can also be associated with types 16, 18, 31, 33 and 35.²⁶ In most cases, genital warts are painless and often unnoticed. In other cases, they can cause pain or irritation.²⁶ Genital warts can appear on the visible or internal genitalia. Common areas of infection include the opening of the vagina, cervix, urethra, perineum, surrounding or inside the anus, the shaft of or under the foreskin of the penis.²⁶

Oral Cancer and Oral Warts

High-risk HPV types (most commonly HPV 16) can contribute to cancer in the mouth and throat, most commonly, at the base of the tongue and tonsils.²⁷ Studies show only about 1% of people have oral HPV that can lead to cancer.²⁷ Low-risk types of HPV can cause warts in the mouth and throat.²⁷ Oral HPV is more common in men than in women.²⁷ It is unclear if HPV infection alone can cause oropharyngeal cancers, or if smoking cigarettes or chewing tobacco interact to cause cancer.²⁷

Penile cancer

HPV has been linked to about half of penile cancers.²⁸ Like oral cancer, most penile cancers are caused by HPV type 16.²⁴

Anal cancer

HPV is responsible for 95% of anal cancers.²⁴ Anal cancer is commonly caused by HPV 16. People who have anal warts are more likely to get anal cancer.²⁹

Vaginal cancer

Approximately 75% of vaginal cancers and precancers are connected with HPV.³⁰

Vulvar cancer

Vulvar cancer occurs on the outer portion of a woman’s vagina, called the vulva. HPV low-risk types 6 and 11 can cause warts on the vulva.³¹ HPV high-risk types are linked to more than half of all vulvar cancers.³¹

Cervical Cancer Screening Recommendations

There are several screening guidelines that have been put forth by national organizations. Globally, cervical cancer screening is far from standardized and is not regulated in many countries. While the WHO provides some guidance on screening and treatment, many countries – especially undeveloped ones – do not adhere to modern techniques.^32,33 Today, after their success in reducing rates of cervical cancer in the US., liquid-based Pap testing and HPV molecular tests are still the most commonly chosen screening methods for cervical cancer screening in the US.^34,35 In most cases, a Pap and HPV test can both be done from a single patient sample collected during a single visit. It is important to understand the distinction between both types of tests.

Pap Testing

The Pap test has greatly reduced the incidence of cervical cancer by detecting abnormal cells on the cervix, often before they develop into precancerous cells or cervical cancer.⁴ During a Pap test:

• Your healthcare provider will collect a sample of cells.
• This sample is then sent to a lab and examined with a microscope for signs of abnormality.
• If abnormal cells are detected, your healthcare provider will discuss treatment options with you.

HPV Testing

HPV testing is done on a molecular level using the same sample taken for the Pap test from the area around the cervix.³⁴ This sample is tested in a specialized machine that detects the presence of those high-risk types that cause cancer.³⁴ It is important to remember that most HPV infections clear on their own, and infection does not mean cervical cancer or even precancer cells are present.¹⁶

Co-testing

HPV and Pap tests are often performed together in what is known as “co-testing.” Regular Pap and HPV screening in accordance with guidelines can help to detect problems early and ensure that you can be treated before cervical cancer develops.

Guidelines for Screening

Certain respected medical organizations have released recommendations for HPV (and Pap) testing. The American Congress of Obstetricians and Gynecologists (ACOG) recommends:

For Women Ages 21-29 years old

Pap testing (without HPV testing) is recommended every 3 years.³⁶ Women in this group may receive HPV testing to determine if patients with certain abnormal Pap results need to receive additional testing.³⁶

For Women Ages 30-65 years old

Pap testing and HPV testing (co-testing) are recommended every 5 years. Pap testing alone is also acceptable every 3 years.³⁶ In some cases, more frequent Pap testing alone may be recommended. The frequency of screening depends on a woman’s health history and her unique risk factors.³⁶

For Women Ages 65 and Older

Women age 65 and older can stop cervical screening if they do not have a history of moderate or severe abnormal cells or cervical cancer and have had either 3 negative Pap test results in a row or two negative co-test results in a row within the past 10 years, with the most recent test performed within the past 5 years.³⁶

Testing Positive for HPV, Abnormal Pap Results, Precancer and Cancer

There are a number of surgical and medical treatments used to treat cervical precancer and cancer. The type of treatment recommended depends on:

• What stage of disease or cancer is present³⁶
• Where it is located on the cervix³⁶
• Whether the cervical cancer is adenocarcinoma or squamous cell carcinoma³⁶
• Each patient’s medical history³⁶
• Each patient’s desire to maintain fertility (ability to have children)³⁶

Once a healthcare provider has a full understanding of a patient’s situation, he or she can better recommend appropriate treatment.

For HPV

If you test positive for HPV infection, you are not alone. While a positive result for HPV can be scary, you are already taking the right steps to protect your health in the future. Remember, you can have HPV without having any type of abnormal cells, cancer or genital warts.³⁷ If your HPV test is positive, your provider will likely order a genotyping test to see if your HPV infection is from one of the highest-risk types.³⁸ If it is high-risk, but you have not developed abnormal cervical cells, you will simply be more closely monitored to ensure you do not develop abnormal cells.³⁸ If, in 12 months, you have no signs of the virus or abnormal cells, you can return to regularly scheduled screening.³⁸ If you have a positive HPV test and abnormal cervical cells, your provider may perform a colposcopy or biopsy to determine if you have precancer or cancer.³⁹ If you do have abnormal cells that put you at risk, your provider may recommend a procedure to remove cells from your cervix.³⁷

For Abnormal Cells or Precancer

Treatments for abnormal cells and cervical precancer include loop electrosurgical excision procedure (LEEP), cold knife conization, cryotherapy and laser therapy.⁴⁰ The goal of each of these procedures, though they are executed differently, is to surgically remove the abnormal cells.⁴⁰

For Cervical Cancer

Treatment for cervical cancer can include those mentioned for precancer.⁴⁰ They may also include cone biopsy, simple (total) hysterectomy, a radical hysterectomy, removal of pelvic lymph nodes, radiation therapy and chemotherapy.⁴⁰ Because each patient’s diagnosis is unique, treatment will depend upon her health and the path she chooses with her healthcare provider’s guidance.

The Risk Factors for Cervical Cancer

There are certain factors that can increase your chance of developing cervical cancer. These factors are a combination of behaviors that can increase the risk of contracting high-risk HPV, factors that can speed up the progress of cervical abnormal cell growth and more. They include

• Smoking or use of other tobacco products⁴¹
• Using birth control for five years or more⁴¹
• Giving birth to 3 or more children⁴¹
• Having several sexual partners⁴¹
• Having human immunodeficiency virus (HIV) ⁴¹

Preventing Cervical Cancer

You should never miss regular screenings with your healthcare provider, including your well woman exam.⁴¹ You can ask your healthcare provider about what type of cervical cancer screening is being performed and stay informed. The CDC recommends that children ages 11-12 should be vaccinated with the HPV vaccine, and everyone under 21 who has not yet been vaccinated.⁴² This two-dose vaccination helps protect against most of the HPV types known to cause cancer.⁴² Additionally, the CDC recommends that all people who are immunocompromised up to age 26 are vaccinated.⁴² While they may not prevent HPV infection, using latex condoms can reduce the likelihood of getting or passing HPV infection to your sex partner.¹⁷ While it will not prevent you from infection with HPV, regular screenings are essential to detect any complications resulting from infection. Your doctor will determine how you can best avoid infection and cervical disease. Remember: You likely have had HPV, have it now or will contract it at some point, like many other people. Make sure you attend your regular doctor visits and ask about cervical cancer screening and which test is right for you.

Congratulations on Learning More

The more you know, the better you can take care of your own health. If you have further questions about your cervical health or sexual health, there are many resources available to you. It is important to stay informed about sexually transmitted infections and the long-term effects they can have on your body. If you would like more information about HPV, cervical cancer or STIs, speak with your healthcare provider. Any questions you have are completely confidential, and your doctor has heard them before. If you would like to read more about HPV, visit the Centers for Disease Control and Prevention website and PapPlusHPV.com.

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