HPV and Oropharyngeal Cancer or Cancer of the
Back of the Throat
- Oropharyngeal Cancer arises from the structures in the back of the throat, normally arise from the epithelium or covering of these structures and for this reasons are mostly squamous cell carcinomas.
- The oropharynx is the structure in the throat at the back of the mouth behind the oral cavity. It includes the back third of the tongue, the soft palate, the side and back walls of the throat, and the tonsils.
- In the US in 2018, there were an expected > 17,500 new cases of oropharyngeal cancer
- This year it is estimated that 10,030 deaths (7,280 men and 2,750 women) will occur from oral and oropharyngeal cancer
- It is recommended that oropharyngeal tumors be tested for HPV
- Human Papilloma Virus, HPV, is transmitted to your mouth by oral sex
- Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) comprises approximately 25% of all head and neck cancers (head and neck squamous cell carcinoma, HNSCC)
Oropharyngeal Cancer arises from the structures in the back of the throat, normally arise from the epithelium or covering of these structures and for this reasons are mostly squamous cell carcinomas. Structures that are commonly affected are the soft palate, side and back wall of the throat, tonsils, and the back third of the tongue.
Human Papilloma Virus, HPV, is the most common sexually transmitted infection in the United States. Of the more than 200 types of HPV, about 40 types can spread through direct sexual contact to genital areas, as well as the mouth and throat. It is important to understand that of all these, only nine are associated with cancers. Of the nine that are high risk, only one is strongly associated with oropharyngeal cancer, HPV16. Oral HPV is transmitted to the mouth by oral sex, or possibly in other ways. Many people are exposed to oral HPV in their life. About 10% of men and 3.6% of women have oral HPV, and oral HPV infection is more common with older age. Most people clear HPV within one to two years, but HPV infection persists in some people.
HPV is thought to be responsible for 25% of mouth cancers and 35% of throat cancers
HPV can infect the mouth and throat and cause cancers of the oropharynx. This is called Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) comprises approximately 25% of all head and neck cancers (head and neck squamous cell carcinoma, HNSCC) or HPV-OSCC (HPV-positive oropharyngeal squamous cell cancer). HPV is thought to cause 70% of oropharyngeal cancers in the United States.
Every day in the US, about 12,000 people ages 15 to 24 are infected with HPV, approximately 26 million Americans on any given day have an oral HPV infection. Of those approximately 2600 are HPV16. The vast majority of individuals will clear the virus naturally through their own immune response, and never know that they were exposed or had it. HPV viral infections also are commonly shared. This means that the partner of someone who tests positive for HPV likely has HPV already, even though they may have no signs or symptoms. Like most Americans, their immune system will customarily clear it in under 2 years.
As in cervical cancer, oral HPV infection appears to be a sexually-acquired disease. Although the natural history of oral HPV infection is not well defined, D’Souza and colleagues recently showed in a case-control study that a high (≥ 26) number of lifetime vaginal-sex partners and 6 or more lifetime oral-sex partners were associated with an increased risk of OPSCC [odd ratio (OR) 3.1 and 3.4, respectively] . An increased risk of HPV-associated OPSCC in female patients with a history of HPV-associated anogenital cancers and their male partners is also consistent with HPV transmission to the oropharyngeal cavity. The recent increased incidence of this disease may thus reflect societal changes in sexual behavior that have occurred over time in the developed world.
An important point to mention is that there is no clear case-control study addressing the evidence for HPV prior to development of OPSCC (i.e. temporal association), with the exception of a Scandinavian study by Mork et al. which showed that the presence of HPV 16 L1 antibodies in pre-diagnostic serum samples was associated with a 14.4-fold increased risk of oropharyngeal cancer. Importantly, the presence of HPV 16 antibodies preceded oropharyngeal cancers by more than 10 years, underscoring a temporal association. These data confirmed that oral HPV infection increases the risk of developing OPSSC.
Lastly, it is possible that in addition HPV infection, other risk factors or cofactors such as genetic susceptibility or nutritional factors or tobacco and alcohol interaction have an important role in cancer onset. There is an objective need for more analytic epidemiological studies in males and females diagnosed with HPV positive oropharyngeal cancer younger than 50 years of age.
Several studies have noted an increased incidence of HPV-associated oropharyngeal cancers, especially tonsillar and tongue cancer. For example, in the USA they have risen by 3.9% and 2.1% among men and women, respectively, in the age group from 20 to 44 years, between 1973 and 2004. Similar patterns have been noted in Sweden for tonsillar cancer which rose 2.9-fold between 1970 and 2001, increasing by 2.6% per year in men and 1.1% in women.
The preference of HPV for the oropharynx is unexplained but may be related to the unique presence of transitional mucosa in the oropharynx, predominantly found in the tonsillar tissue and which shows histological similarities to the cervical mucosa. Another possibility lies within the genetic features of HPV 16, which accounts for more than 90-95% of all HPV associated oropharyngeal cancers, as it may facilitate survival in the tonsillar crypt epithelium. It is also possible that the invagination of the mucosal surface of the tonsil may favor virus capture and maintenance by promoting its access to basal cells (the only dividing cells in the epithelium). If this is true, tonsillar tissue could be a reservoir for HPV in the upper aerodigestive tract. This view is partly supported by the fact that when oral samples are collected by an oral rinse, the detection rate of HPV is much higher than with swabs. Finally, the persistence of HPV in tonsillar tissue might be of importance in the immune response to HPV.
Recent global genomic screening studies searching for a biological distinction among HPV-positive and negative OPSCC have shown that HPV-induced carcinogenesis has a clear impact on the acquisition and maintenance of specific chromosomal gains and losses within tumor cells, in which OPSCCs with transcriptionally active HPV DNA are characterized by occasional chromosomal loss/ allelic imbalance. Conversely, those lacking HPV-DNA are characterized by gross deletions that involve entire or large parts of chromosomal arms.
The biology of HPV-positive oropharyngeal cancer is typified by p53 degradation, retinoblastoma protein (RB) down-regulation and p16 up-regulation. By contrast, tobacco-related oropharyngeal cancer is characterized by p53 mutations, down-regulation of p16 and RB up-regulation. Interestingly, recent studies observed an inverse correlation between the presence of HPV and p53 mutations.
Clinical stage at presentation
Multiple studies have shown that HPV-positive tumors are more likely to present with early T stage (T1-T2) and higher N stage (usually cystic and multilevel), and have distinct histological features, such as moderate/poor tumor differentiation and non-keratinising or basaloid pathology. The incidence of distant metastases was seen to be lower in patients with HPV positive tumors. Furthermore, metastases developed later and with a very different pattern from patients with HPV-negative tumors. The HPV-positive oropharyngeal cancer had a 28% reduction in the risk of death and a 49% reduction in the risk of disease recurrence. Secondary primary tumor (SPT) in patients with HPV-positive cancer is very rare and has improved better survival rate compared to patients with HPV negative tumors.
Recent studies have shown the radiological difference between HPV-positive and HPV-negative oropharyngeal cancer. Specifically, HPV-positive carcinomas often had small or even occult primary lesions with well-defined borders and cystic nodal metastases, whereas HPV-negative primaries more often had poorly defined borders and invasion of adjacent muscle 52 54.
It usually takes years after being infected with HPV for cancer to develop. It is unclear if having HPV alone is enough to cause oropharyngeal cancers, or if other factors (such as smoking or chewing tobacco) interact with HPV to cause these cancers.
There are vaccines available to protect you from HPV
To reduce your risk of HPV infection, limit your number of sexual partners. Having many partners increases the risk of HPV infection. Using a condom does not fully protect you from HPV during sex. It is also likely that receiving an HPV vaccination before exposure to HPV can reduce the risk of oropharynx cancer. The Centers for Disease Control and Prevention has recommended HPV vaccination for all preteen boys and girls.
FDA restricts the manufacturers from talking about other potential positive implications of these vaccines in different anatomical sites that HPV is known to infect. Since these vaccines block people from ever getting HPV16, it is not much of a scientific leap to extrapolate that to “if you can’t get the virus, you can’t get things the virus might cause”. Using this logic, many in the science community, including the CDC, and every major cancer treatment center in America, recommend vaccinating to protect people from the various different cancers associated with the virus such as oropharyngeal and anal cancers. The foundation also believes this to be highly worthy of doing, and has advocated at the CDC for vaccination of boys (finally winning their approval for pediatricians and other doctors to do so), not only to more quickly help reach the point of “herd immunity” in our country; protecting our next generation from HPV caused cervical cancers, but also to offer protection from other HPV cancers as well including oropharyngeal.
How frequent are Oral and Oropharyngeal Cancers?
Head and neck cancer account for approximately 4% of all cancers in the United States. The estimated incidence of head and neck cancer in 2017 was 65,000. Cancer of the oral cavity is the eighth most common cancer among men. In the US in 2018, there were an expected > 17,500 new cases of oropharyngeal cancer. Although the incidence of oropharyngeal cancer is increasing, its cure rates are also improving. The male:female ratio is > 2.7:1. There has been an increase in HPV-related oral and oropharyngeal cancers among white men and women. It is estimated that 10,030 deaths (7,280 men and 2,750 women) from these 2 diseases will occur this year.
The overall frequency of head and neck cancer is quite high and accounts for more than 550, 000 cases annually worldwide.
Males are affected significantly more than females with a ratio ranges from 2: 1 to 4: 1.
What are the causes and risk factors for Oral and Oropharyngeal Cancer?
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk to your doctor if you think you may be at risk. Oropharyngeal is considered a multifactorial entity. The risk of oral and oropharyngeal cancer is greatly increased by 2 factors. The most common causes and risk factors include the following:
1. Smoking: E heavy cigarette smokers, there is a 5- to 25 fold increase of cancer compared to with non-smokers. 75% of all cases of head and neck cancer in the United States are associated with smoking and alcohol. As with most head and neck cancers, non-HPV related oropharyngeal cancer is more common among older men, with a median age of 61. Tobacco and alcohol remain important risk factors for oropharyngeal cancer. Patients who smoke more than 1.5 packs/day have about a 3-fold increased risk of cancer, and patients who drink 4 or more drinks/day have about a 7-fold increased risk. People who both drink and smoke heavily have 30 times the risk of developing oropharyngeal cancer.
- Alcohol: Alcohol consumption independently increases the risk of cancer in the upper digestive tract.
- Viral infections
- Epstein-Barr virus: Large body of evidence supports the role of Epstein-Barr virus as the primary etiology agent in the pathogenesis of nasopharyngeal carcinoma.
- human papillomavirus, HPV: HPV now causes most oropharyngeal cancers in the U.S. There are different types of HPV, called strains. Immunologic molecular evidence has established a causal role for HPV, primarily type 16, in patients with head and neck cancer particularly those arising in the base of the tongue and tonsils. HPV type 16 causes 60% of oropharyngeal cancers, and patients have become younger (median age 57 yr, and bimodal peaks at 30 yr and 55 yr) as HPV infection has emerged as an etiology. HPV associated oropharyngeal cancers are typically seen in younger men who are nonusers of the tobacco. In the United States, the incidence of oropharyngeal cancer caused by HPV infection is increasing, while the incidence of oropharyngeal cancer related to other causes is falling. Over 20 million Americans have some type of genital or oral HPV infection. HPV is a sexually transmitted infection that can infect the oropharynx (tonsils and back of the throat), anus, and genitals. The risk of developing oropharyngeal cancer is 16 times higher in HPV-positive patients. In Europe and North America, HPV infection accounts for about 70 to 80% of oropharyngeal cancers. In some people with oral HPV infection, leads to HPV-OSCC (HPV-positive oropharyngeal squamous cell cancer) after many years. It is recommended that oropharyngeal tumors be tested for HPV. HPV is transmitted to your mouth by oral sex. It may also be possible to get oral HPV in other ways. Performing oral sex and having many oral sex partners can increase your chances of oral HPV infection. Around 10% of men and 3.6% of women in the U.S. have HPV in their mouths and HPV infection is more commonly found with older age. Most people clear the infections on their own within a year or two, but in some people, HPV infection persists. Oropharyngeal cancer patients with HPV in their tumor live longer, on average than people without HPV (i.e. HPV-positive tumors usually respond well to therapy). However, patients who currently smoke tobacco or have smoked for a long time in the past do not live as long as patients who never smoked. Patients who are current smokers should consider quitting.
- Human immunodeficiency virus: There is an approximately 2-3 fold increase in the incidence of a squamous cell carcinoma of the head and neck in HIV- infected patients
- Occupational exposure: Exposure to dry cleaning agent perchloroethylene, asbestos, pesticides, polycyclic aromatic hydrocarbons, textile workers, woodworkers, metals, ceramics, food industry, and login
- Squamous cell carcinoma of the larynx and base of the tongue has also been associated with exposure to agent orange.
- Genetic and hereditary factors can be associated with throat and mouth cancer. The analysis of the genes in head and neck cancer was based on public currently available gene expression data and clinical made at data from the Cancer Genome Atlas, consisting of 499 patients. According to the analysis, 792 genes were associated with prognostic outcome, out of which 341 images were associated with unfavorable prognosis and 451 with a favorable prognosis. The LIMA 1 gene, a cytoskeletal-associated protein is associated with an unfavorable prognosis. CALM L5, calcium binding protein that may be implicated in different deviation of keratinocytes, shown to be associated with a favorable prognosis. The NOTCH is a common mutation found
In squamous cell carcinoma of the head and neck; this is a genetic mutation has also been previously implicated in a number humans tumor type, including colon, breast, and pancreatic cancers.
What are the types of Oropharyngeal Cancer?
Squamous cell carcinomas account for 90 to 95 percent of the lesions in the head and neck. They can be categorized as well differentiated (greater than 75 percent keratinization), moderately differentiated (25 to 75 percent keratinization), and poorly differentiated (less than 25 percent keratinization) tumors. Less common histologies include verrucous carcinoma (a variant of squamous cell carcinoma), adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinomas. There is a type of cancer referred to as HPV-OSCC (HPV-positive oropharyngeal squamous cell cancer) . It is recommended that oropharyngeal tumors be tested for HPV.
What are the symptoms and signs of Oropharyngeal Cancer?
Symptoms can vary according to location
- Red or white patch on the gums, tongue, tonsil, or lining of the mouth
- Lump on the throat or a feeling of thickening in the cheek
- A persistent sore throat or feeling that something is caught in the throat
- Hoarseness or change in voice
- Numbness of the mouth or tongue
- Pain or bleeding in the mouth
- Difficulty chewing, swallowing or moving the jaws or tongue
Facial and/forehead pain may be seen in later stages, due to pressure or tumor infiltration into nerves or periosteum.
How is Oropharyngeal Cancer diagnosed?
A thorough physical exam is essential along with an endoscopy examination. The endoscope allows the doctor to see inside the mouth and throat. Typically, a thin, flexible tube with an attached light and view lens, called an endoscope, is inserted through the nose to examine the head and neck areas. o make the patient more comfortable, these examinations are performed using an anesthetic spray to numb the area. If an area looks suspicious, the doctor will take a biopsy. Tests are often done in the doctor’s office. However, sometimes an endoscopy must be performed in an operating room at a hospital using general anesthesia, which blocks the awareness of pain.
If your doctor sees any suspicious lesion a biopsy is performed. A biopsy is the only sure way for the doctor to know whether an area of the body has cancer. In a biopsy, the doctor takes a small sample of tissue for testing in a laboratory by a pathologist.
Fine needle aspiration cytology—Fine needle aspiration cytology (FNA) is frequently used to make an initial tissue diagnosis of a head and neck cancer when a patient presents with a neck mass (metastatic cervical lymph node) without an obvious site.
Imaging studies—Imaging studies.
(computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET], and integrated PET/CT)are important for assessing the degree of local infiltration, the involvement of regional lymph nodes, and presence of distant metastases or second primary tumors.
Computed tomography (CT or CAT) scan creates a 3-dimensional picture of the inside of the body using x-rays taken from different angles. A computer combines these images into a detailed, cross-sectional view that shows any abnormalities or tumors. A CT scan can be used to measure the tumor’s size, help the doctor decide whether the tumor can be surgically removed, and show whether the cancer has spread to lymph nodes in the neck or lower jawbone. Sometimes, a special dye called a contrast medium is given before the scan to provide better detail on the image. This dye can be injected into a patient’s vein or given as a liquid to swallow.
Magnetic resonance imaging (MRI) uses magnetic fields, not x-rays, to produce detailed images of the body, especially images of soft tissue, such as the tonsils and the base of the tongue. MRI can be used to measure the tumor’s size. A special dye called a contrast medium is given before the scan to create a clearer picture. This dye can be injected into a patient’s vein or given as a liquid to swallow.
Ultrasound uses sound waves to create a picture of the internal organs. This test can detect the spread of cancer to the lymph nodes in the neck, called the cervical lymph nodes.
Positron emission tomography (PET) or PET-CT scan is usually combined with a CT scan However, you may hear your doctor refer to this procedure just as a PET scan. A PET scan is a way to create pictures of organs and tissues inside the body. A small amount of a radioactive sugar substance is injected into the patient’s body. This sugar substance is taken up by cells that use the most energy. Because cancer tends to use energy actively, it absorbs more of the radioactive substance. A scanner then detects this substance to produce images of the inside of the body.
HPV testing. HPV testing may be done on a sample of the tumor removed during the biopsy. HPV has been linked to a higher risk of oropharyngeal cancer. Whether a person has HPV can help determine cancer’s stage and the treatment options that are likely to be most effective. It is recommended that HPV testing is done for all patients newly diagnosed with oropharyngeal squamous cell carcinoma. This is a type of oropharyngeal cancer that starts in flat, scale-like cells called squamous cells. Testing is not usually recommended for oropharyngeal cancer that starts in other types of cells or for other types of head and neck cancer.
Testing for Oral HPV
There are many oral cancer screening devices and tests, currently, none of them can find HPV positive oral and oropharyngeal cancers early. There are oral HPV infection tests on the dental market, and while they will find an oral HPV infection which as many as 26 million Americans have on any given day, (NHANES study, ongoing), that is no indicator that a person will cascade into an oral/oropharyngeal cancer. The foundation feels that while these tests find infections through a well-recognized testing protocol (PCR testing), since only about 1% of individuals that develop a high risk type oral HPV infection ever cascade into cancer, and that most often occurs decades after infection, that the utility of the test is highly in question when in it comes to providing meaningful and actionable information. The best way to screen for HPV related oral and oropharyngeal cancer today is through a visual and tactile exam given by a medical or dental professional, who will also do an oral history taking to ask about signs and symptoms that cover things that are not visible or palpable. Most of the symptoms of a developing HPV positive infection are discovered by asking questions not using a test, a light or other device to do so. Like other cancer screenings you engage in, such as cervical, skin, prostate, colon and breast examinations, opportunistic oral cancer screenings are an effective means of finding cancer at its early, highly curable stages. However like many other cancer screening techniques, this process is not 100% effective, is highly problematic in HPV origin disease, and any screening technique or technology can miss things. This is why it is so important that persistent problems, those which do not resolve in a short period of time like 2-3 weeks, are pursued until a definitive diagnosis of what it is, is established. Most of the time these will be issues that are not cancer, but persistent problems need to be addressed, cancer or not.
Staging for Oropharyngeal Cancer
- After oropharyngeal cancer has been diagnosed, tests are done to find out if cancer cells have spread within the oropharynx or to other parts of the body.
- There are three ways that cancer spreads in the body.
- Cancer may spread from where it began to other parts of the body.
- The following stages are used for oropharyngeal cancer:
- Stage 0 (Carcinoma in Situ)
- Stage I. The cancer is 2 centimeters or smaller and has not spread outside the oropharynx.
- Stage II. The cancer is larger than 2 centimeters, but not larger than 4 centimeters and has not spread outside the oropharynx.
- Stage III. Cancer is larger than 4 centimeters and has not spread outside the oropharynx. An alternate form of this stage is that cancer is any size and has spread to only one lymph node on the same side of the neck as the cancer. The lymph node that contains cancer is 3 centimeters or smaller.
- Stage IV. This stage contains the sub-stages of IVA, IVB, and IVC:
- Stage IVA In Stage IVA, one of the following is the case:
- The cancer has spread to tissues outside the oropharynx, including the voice box, roof of the mouth, jaw, muscle of the tongue, or central muscles of the jaw. The cancer may have spread to one or more nearby lymph nodes, which are still not larger than 6 centimeters.
- The cancer is any size, is only in the oropharynx, and has spread to one lymph node that is larger than 3 centimeters but no larger than 6 centimeters, or to more than one lymph node, none larger than 6 centimeters.
- Stage IVB In Stage IVB, one of the following is true:
- The cancer appears in a lymph node that is larger than 6 centimeters and may have spread to other tissues around the oropharynx.
- The cancer surrounds the main artery in the neck or has spread to bones in the jaw or skull, to muscle in the side of the jaw, or to the upper part of the throat behind the nose. The cancer may have spread to nearby lymph nodes.
- Stage IVC In Stage IVC, the cancer has spread to other parts of the body. The tumor may be any size and may have spread to lymph nodes.
- Stage IVA In Stage IVA, one of the following is the case:
The tumor node metastases(TNM) staging system of the American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control (UICC) is used to classify cancers of the head and neck.
T classifications indicate the extent of the primary tumor and are site-specific.
The overall 5-yr survival rate is about 60%. The 5-year survival rate refers to the percentage of patients who live at least 5 years after their cancer is diagnosed. Of course, many of these people live much longer than 5 years. However, the prognosis varies with the cause. Patients who are HPV-positive have a 5-yr survival of > 75% (and a 3-yr survival of almost 90%), whereas HPV-negative patients have a 5-yr survival of < 50%. The higher survival with HPV-positive cancer is due to a favorable tumor biology and a younger, healthier patient population. High expression of p16 appears to improve the prognosis for both HPV-positive and HPV-negative oropharyngeal tumors. HPV-positive tumors have higher radiosensitivity, probably due to intact apoptotic response to radiation
Treatment for Oropharyngeal cancer?
Treatment for head and neck cancer is complex due to the Variety of tumor subsites and anatomic constraints of the head and neck. The Importance of maintaining organ function. A multidisciplinary approach including
EARLY STAGE: Approximately 30 to 40 percent of patients with head and neck squamous cell carcinomas (HNSCCs) present with early (stage I and II) disease.
In general, these patients are treated with either primary surgery or definitive radiation therapy(RT). Five-year overall survival in patients with stage I or stage II disease is typically 70 to 90 percent.
ADVANCED STAGE: Effective approaches for locoregionally advanced head and neck squamous cell carcinomas include
Primary surgery followed by either postoperative RT or concurrent chemoradiation. Surgery is increasingly being used as the primary treatment of oropharyngeal cancer. Transoral laser microsurgery (TLM) is increasingly being used to resect tumors of the tonsil and base of tongue endoscopically, avoiding the morbidity of open surgery. Transoral robotic surgery (TORS) is an increasingly popular means of treating select oropharyngeal lesions. In TORS, a surgical robot with multiple adaptable arms is controlled by a surgeon at a console. The articulating arms of the robot and an endoscopic camera are inserted through the patient’s mouth (which is held open by a retractor). The robotic procedure provides better visualization of structures and causes less surgical morbidity compared to open surgery. However, the indications for using TORS are not yet well defined. When TORS is used on patients with more advanced tumors, postoperative radiation or chemoradiation is often done.
Induction chemotherapy followed by concurrent chemoradiotherapy
Neo (adjuvant –in addition to) chemotherapy the drugs may shrink the tumor and give more surgical options.
What are the side effects of treatment of head and neck cancer?
Surgery and chemoradiation have a variety of the effects on patients. It often changes the patient’s ability to swallow chew, swelling of the neck, or talk.
Redness, irritation, sores in the mouth, difficulty swallowing, changes in taste, or nausea are the changes in patients who have received radiation to the head and neck. If There are changes should be reported to the doctor and nurses so you can learn how to deal with them.
The information in this document does not replace a medical consultation. It is for personal guidance use only. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of the disease.
- American Cancer Society
- The National Cancer Institute
- National Comprehensive Cancer Network
- American Academy of Gastroenterology
- National Institute of Health
- MD Anderson Cancer Center
- Memorial Sloan Kettering Cancer Center
- American Academy of Hematology