What is Adjunctive Oral Cancer Screening?

What Exactly is Adjunctive Oral Cancer Screening?

With the rise of oral cancer cases in North America, largely attributed to a strain of the human papillomavirus (HPV), oral cancer screening is more important than ever before. In fact, the American Dental Association recommends a visual and tactile comprehensive oral examination (COE) to be routinely performed to support early discovery and diagnosis of oral cancer and/or pre-cancer in patients of dental practices[1]. This visual and tactile examination is the absolute minimum dental practices should do for their patients concerning oral cancer screening. Adjunctive oral cancer screening technologies are used in conjunction with the COE to help detect abnormalities and provide additional information to be utilized in the clinical decision-making process.

The Purpose of Adjunctive Oral Cancer Screening

It is essential to understand that adjunctive screening should never be performed without a thorough physical examination of the oral cavity under white light accompanied with a tactile assessment of the head, neck and oral cavity.

The majority of adjunctive screening methodologies are non-diagnostic, meaning they will not give a positive or negative result in relation to whether a patient has oral cancer. Because oral cancer can often go unnoticed to the naked eye, many adjunctive technologies aim to enhance the visualization of these areas of concern so that they will be more noticeable and, hopefully, reduce the likelihood that abnormal mucosa is overlooked. The information provided by adjunctive screening together with the information from the COE is then used to contribute to the clinician’s decision-making process for referring patients to a specialist for biopsy.

Types of Adjunctive Oral Cancer Screenings Technologies

There are several different adjunctive screening technologies that can be utilized to aid in visualizing oral abnormalities, including:

  • Vital tissue staining
  • Chemiluminescence
  • Autofluorescence
  • Cytopathology

Vital Tissue Staining 

Vital tissue staining utilizes a chemical called Toluidine Blue (ToB), which is a dye that is absorbed by unhealthy mucosa, giving areas of concern a dark blue color. These dark areas are then considered to be areas of concern that warrant further investigation.

Chemiluminescence 

Chemiluminescence, marketed under the brand Vizilite, is considered the first adjunctive device for oral screening that hit the market around 15 years ago. This technology combines application of an acetic acid solution with the use of a blue-white light to help identify abnormal mucosa. The acetic acid solution is swished in the mouth for 1-2 minutes, dehydrating the mucosa to accentuate keratinized tissue. A chemiluminescent light is then utilized to accentuate oral mucosal abnormalities.

Autofluorescence 

Autofluorescence relies on the use of specific wavelengths of light interacting with fluorophores that are naturally present in most human tissues. When exposed to certain light wavelengths, fluorophores become excited and re-emit light of varying colors. Abnormal mucosa impacts the spectral properties of the tissue, allowing detection through special optical filters. The VELscope is an example of an autofluorescence technology, in addition to the Vizilite Pro and Oral ID systems.

Cytopathology

Another adjunct to the traditional COE is cytopathology, which involves the collection of cells from a suspected lesion and viewing them under a microscope to inspect for abnormalities. One example of a cytopathology system is the Oral CDx Brush Test, which uses a special brush to remove cells from a suspected lesion which are then sent to a lab for microscopic review.

Role of Biopsy

Biopsy is the gold-standard for histopathologic diagnosis of lesions . It involves physical sampling of the suspect tissue, samples of which are then examined by a pathologist under a microscope who produces the histopathologic diagnosis.  This diagnosis and consideration of patient history is then used to plan appropriate treatment for the patient.

Effectiveness of Adjunctive Screening Technologies

The COE is certainly aided by the incorporation of adjunctive technologies with regard to identifying oral mucosal abnormalities. While the COE is often efficient in locating areas of concern that are obvious to the naked eye, there is increased difficulty observing less obvious lesions or abnormalities. The addition of an adjunctive technology helps make visualization of abnormal tissues more apparent.

A study in the Journal of the American Dental Association[2] argues that the comprehensive visual and tactile examination performs poorly in locating oral squamous cell carcinomas in their earliest stages, where treatment and outcomes are more favorable. The researchers conclude that the comprehensive oral examination could be improved with the implementation of adjunctive technologies, which can subsequently contribute to the visualization of dysplastic lesions.

Again, neither the COE nor adjunctive screening technologies provide a definitive diagnosis as to the exact nature of the abnormality but can assist in providing information that can be utilized in the referral decision-making process.

So What is Adjunctive Oral Cancer Screening?

To conclude, adjunctive oral screening is an additional process that provides supplemental information to be used in conjunction with a COE. Adjunctive technologies can also help ensure that areas of concern do not go unnoticed and are visualized in early stages. By taking a holistic view of all information obtained through acquisition of patient medical history, the COE and adjunctive screening, clinicians can make more informed decisions regarding patient referral and treatment.

Want to learn more about oral screening and adjunctive technologies, including the VELscope? Contact our team below or give us a call at 877.278.3799.

1https://www.ada.org/en/member-center/oral-health-topics/cancer-head-and-neck

2 Epstein, et al. The limitations of the clinical oral examination in detecting dysplastic oral lesions and oral squamous cell carcinoma. JADA. 2012; 143. 1332-1342

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How Do I Know if It’s Oral Cancer? 5 Simple Steps

The headline news in today’s world is daunting to say the least. “The Startling Rise in Oral Cancer in Men”, “Oral Cancer Rates Rise by Two-Thirds”, “What’s Behind the Huge Rise in Oral Cancers?’ just to quote a few. What if we do find something unusual or different inside our mouth? How do I know if it’s oral cancer?

  1. The finding resolves on its own.  First rule of thumb is persistence. Anything unusual that persists beyond 14 days should always be investigated. A trip to your dentist to further evaluate a finding is critical. At that time the dentist may be able to identify the cause or may choose to evaluate further through the means of a small sampling of tissue or a biopsy. Either way, this needs to be addressed. Don’t wait!
  2. The finding is on both sides of the mouth. If the identifying lesion is present on both sides of the mouth, it is most likely part of the normal anatomical makeup. Asymmetry or presence on only one side raises more of a concern.
  3. The finding is initiated by trauma. An unusual finding may be caused by trauma; something as simple as biting your cheek or burning the palatal tissue with a slice of hot pizza can bring an area of the mouth to our attention. Again something of this nature should resolve within 7 – 10 days on its own and if it persists for more than 14 days, seek further evaluation.   
  4. The finding recurs and subsequently resolves on its own. A recurring sore that repeatedly resolves on its own is most likely initiated by trauma, stress or sometimes dietary aspects and is referred to as an aphthous ulcer or canker sore.  Typically a canker sore will last 7 – 10 days with the acute pain occurring when the lesion ulcerates. This happens in the middle of the duration of the canker sore and usually lasts 3 – 4 days.   
  5. The finding accompanies an illness and resolves on its own. There are a number of different illnesses that are accompanied by oral lesions or sores that may be found throughout the mouth. Typically the patient is experiencing general malaise, fever and would be directed to see a physician. The lesions once again resolve on their own.

Chances are if a finding meets the criteria above it is not oral cancer however there is only one way to know for sure and that is through further professional investigation. 

The point here is that in today’s world with oral, tonsillar and throat cancer on the rise, it is prudent to be knowledgeable and aware. Self examination between dental visits is vitally important as it allows for earlier discovery of anything abnormal. An oral cancer screening examination which includes checking the lymph nodes of the neck should be done on an annual basis.

Additional screening with a device such as VELscope which enables the dentist or dental hygienist to see beneath the surface where abnormal cells begin to develop provides an enhanced opportunity to again discover oral cancer in its earliest possible stage. To find a practice near you that offers the VELscope Vx examination, visit our Find a Practice Tool and enter your postal or zip code.   

Author: Jo-Anne Jones

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Is the COE Part of Your Routine?

The conventional intra and extra oral head and neck examination is taught in dental and hygiene schools to screen patients for oral cancer and other oral mucosal disease. It normally consists of a visual inspection of oral tissue, or oral mucosa, under incandescent or halogen light using the naked eye to look for suspicious lesions, as well as extra oral palpation of the face and neck to feel for suspicious lumps and intra oral palpation of the mucosa.

So why is it important? A 3-4 minute visual and palpation exam is crucial in the early detection of oral diseases. It is quick to perform, painless for the patient, and enhances the patient experience with the dental practice.

According to the Oral Cancer Foundation nearly 42,000 Americans will be diagnosed with oral or pharyngeal cancer this year. The percentage of oral cancer patients who ultimately die of the disease is higher than that of many other cancers. The key to reducing the number of lives lost to oral cancer is earlier detection of the disease, and the key to earlier detection is more frequent and more thorough intra and extra oral head and neck exams. Currently, the majority of oral cancers are detected in the later stages, when the five-year survival rate is only about 50 percent. What’s the good news? When discovered early, the survival rate leaps to around 82 percent.

There is a growing body of research available on the importance of the Clinical Oral Exam (COE) and the increased demand for comprehensive COE’s. The results from a recent independent survey have indicated that the majority of patients say they have never had an oral cancer exam. A recent UK survey found that “92% percent of respondents would like their Dentist to tell them if they were being screened for signs of oral cancer and 97% would like help from their Dentists to reduce their risk.” (1)

The take away from this study is that the majority of people are in favor of COE’s and place value in the dental health professional being involved in the oral cancer screening process. Learn how you can improve your COE. Stay ahead of the curve by screening for oral disease and oral cancer using an adjunctive device and help patient outcomes through early detection.

(1)   Oluwatunmise Awojobi*, Suzanne E Scott and Tim Newton, ‘Patients’ Perceptions of Oral Cancer Screening in Dental Practice: a Cross-sectional Study’, (BMC Oral Health 2012), http://www.biomedcentral.com/1472-6831/12/55

 * Tissue Fluorescence Image Courtesy of Dr. Samson Ng.

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Early Detection Can Equal Higher Survival Rates

It is a disease that we give very little thought to, but oral cancer continues to be prevalent with approximately 42,000 Americans being diagnosed with oral cancer or oral pharyngeal cancer this year. It will cause over 8,000 deaths, killing roughly 1 person every hour. Of those 42,000 newly diagnosed individuals, only slightly more than half will be alive in 5 years (Approximately 57%). This is a number which has not significantly improved in decades. Increasing oral cancer screenings can decrease the mortality rates from oral cancer. Early Detection is the key to better treatment, better outcomes and higher survival rates.

With early detection and timely treatment, deaths from oral cancer could be dramatically reduced. The 5-year survival rate for those with localized disease at diagnosis is 83 percent compared with only 32 percent for those whose cancer has spread to other parts of the body. It is important to open this discussion with patients and even if it’s not causing any pain, any discoloration, swelling, spots, ulcers or lumps that have been there for longer than two weeks should be checked out more thoroughly.

Oral cancer does not discriminate and an oral or oropharyngeal cancer can appear anywhere throughout the oral cavity, including the lips, the lining of the mouth, both under and on top of the tongue, in the back of the throat, tonsils, roof of the mouth and also within the gums, including the area behind the wisdom teeth. Regular screening and thorough documentation performs a key role in the early stages of detection and diagnosis.

The death rate from this type of cancer is high because it is often discovered late in its development, generally when it has spread to another location like the lymph nodes of the neck. At this stage the prognosis can be significantly worse. The good news is oral cancer can be readily diagnosed. In many cases cancer screening can be invasive, but unlike other forms of cancer, the oral cancer screening process is much easier and less invasive. With a comprehensive COE and good documentation it is easy to be diligent about any “area of concern” in the oral cavity.

The healthcare professional best positioned to screen for oral disease and cancer, are dentists and/or dental hygienists. Incorporating the COE into the routine dental visit seems to be the most effective way to tackle the early detection of oral disease and oral cancer. Nurse Practitioners, Physician Assistants, Primary Care or Family Physicians, Urgent Care Physicians, Otolaryngologists (ENT), Head and Neck Surgeon and Gastroenterologists are also professionals engaging in the fight against oral cancer. Make the COE discussion part of the patient relationship, it’s a great way to show that we as health care professionals truly care about our patients.

[1] National Institute of Dental and Craniofacial Research ‘Detecting Oral Cancer: A Guide for Health Care   Professionals’, (nidcr.nih.gov, Bethesda, MD), http://www.nidcr.nih.gov/oralhealth/topics/oralcancer/detectingoralcancer.htm


Dr. John Roberson
 is  a committed professional when it comes to early detection of oral mucosal disease and oral cancer. He is an award winning Board Certified Oral & Maxillofacial Surgeon, and also has Board Certification from the National Dental Board of Anesthesiology.  He is a member of the American Association of Oral & Maxillofacial Surgeons, American College of Oral & Maxillofacial Surgeons, American Dental Association, Mississippi Dental Association, and the South Mississippi Dental Association. Learn more about his practice and dedication at www.drjohnroberson.com

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Clinical Study Concludes That VELscope™ Technology Improves Clinical Decision Making

Independent clinical study by seven researchers from the University of British Columbia, British Columbia Cancer Agency and Simon Fraser University, is the latest report to document the benefits of adjunctive oral examination technology. The lead researcher for the study was Denise M. Laronde RDH MSc, of the Department of Oral Biological and Medical Sciences, Faculty of Dentistry, at the University of British Columbia. The study concluded that integrating fluorescence visualization technology, as delivered by the VELscope® Vx, significantly improves the protocol for screening, assessing and reassessing oral lesions.

The goal of the study was to determine whether the VELscope’s fluorescence visualization (FV) technology added any value to the traditional intraoral and extraoral examination for oral cancer screening. The researchers’ questions were focused on whether positive FV results were associated with persisting lesions detected through a step-by-step procedure that included both a conventional oral examination and an adjunctive examination using VELscope® Vx technology.  The study concluded the following:  “A protocol for screening (assess risk, reassess, and refer) is recommended for the screening of abnormal intraoral lesions. Integrating FV into a process of assessing and reassessing lesions significantly improved this model.”(1)

The full article, “Influence of Fluorescence on Screening Decisions for Oral Mucosal Lesions in Community Dental Practices,” was published in the Journal of Oral Pathology & Medicine and is also available through the LED Dental website by visiting the Downloads Center.

Peter Whitehead, founder of LED Medical Diagnostics and its subsidiary, LED Dental is encouraged by the study, “Many clinicians are unaware of the significant benefits that the adjunctive use of VELscope™ can bring to the table. It is nice to see independent confirmation that the use of VELscope™ technology not only enhances early detection but also supports clinical decision making as well.”

(1)   DM Laronde, PM Williams, TG Hislop, C Poh, S Ng, C Bajdik, L Zhang, C Macaulay, MP Rosin, Influence of fluorescence on screening decisions for oral mucosal lesions in community dental practices, (Vancouver, Canada, University of British Columbia, September, 2013)

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Oral health warning

Three signs your mouth ulcer is cancerous

One of the primary symptoms of mouth cancer relates to the ulcers in the mouth. If these are painful and do not heal within several weeks, it could be a sign of mouth cancer. Furthermore, lumps that are unexplained, persistent or do not go away, are also signs of the condition say the NHS. Unexplainable loose teeth or tooth sockets that don’t heal after extractions are other symptoms of mouth cancer. Mouth cancer is one of the least common cancers in the US or UK, but it’s essential to know the symptoms.  Additionally, a person with the disease may feel a persistent numbness on the lip or tongue. Occasionally, red, or white patches may appear on the lining of the tongue or mouth in patients with mouth cancer. Read more about variables that impact your oral health.

Person smiling and mouth.

The final symptom of mouth cancer is changes in a person’s speech, such as a lisp.

Other symptoms of mouth cancer include:
• Pain or difficulty swallowing
• Bleeding or numbness in the mouth
• Difficulty moving the jaw
• Changes in the voice.

Similarly to other cancers, there are different types of mouth cancer. Each form of mouth cancer is named after the cell that the cancer starts to grow in. The most common form of mouth cancer is squamous cell carcinoma. This type of cancer makes up 90 percent of mouth cancer cases.

Squamous cell carcinoma can be found in the skin as well as inside the mouth. Other types of mouth cancer include adenocarcinoma, sarcoma, oral malignant melanoma and lymphoma. Adenocarcinoma develops inside the salivary glands. Sarcoma is a cancer that develops out of abnormalities in bone, cartilage, muscle and other tissue.

Mouth cancer infographic.

Factors that increase a person’s risk of mouth cancer and oral health include:
• Smoking
• Chewing tobacco
• Drinking alcohol
• HPV virus infection
• Unhealthy diet
• Bad oral hygiene.

Original Article

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What is oral cancer, the condition John Farnham is being treated for?

Seventy three-year-old Australian music icon John Farnham is in a stable condition in intensive care after undergoing surgery to remove an oral cancer. Farnham’s family paid tribute to the health-care professionals after more than 11 hours of surgery on Tuesday.

Original Article

Farnham’s diagnosis comes as a shock to many, there is little public awareness about oral cancer and the broader range of head and neck cancers. 

So what is it? Who is more likely to be diagnosed with it? And what does recovery or rehabilitation look like? 

Oral cancer is one type of head and neck cancer. While we can’t comment on Farnham’s condition specifically, we’re speech pathologists and researchers with experience working with our teams to support other patients with these cancers and guiding them through their recovery. 

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What is head and neck cancer? How common is it?

Head and neck cancers most commonly begin in the cells lining the mouth (oral cavity), nose and sinuses, throat (pharynx) or voice box (larynx). 

Risk factors for head and neck cancer include smoking, excessive alcohol consumption, and being infected with the human papillomavirus (HPV). But some patients may have no identifiable cause for their cancer. 

In Australia, almost 4,000 people are diagnosed with head and neck cancer each year, and this number is increasing

Globally, the impact of head and neck cancer disproportionately affects those in developing countries due to increased risk factors, delays in diagnosis and limitations on interventions. 

Cancers of the head and neck have typically been more common in men over the age of 65. However, an increase in cancers related to infection with HPV, the most common sexually transmitted infection, has seen a change in these demographics to include younger people. 


Read more: Health Check: can sex affect your risk of getting cancer?


Unfortunately, these cancers do not always receive the same media and philanthropic attention as other cancers.

What are the symptoms and treatments?

Finding cancer early is important but unfortunately, there are no formal screening tests for head and neck cancer.

Common signs and symptoms can include a neck lump, a lump or sore that does not heal, a red or white patch in the mouth, trouble speaking or using your voice, or difficulty breathing. Always speak to your doctor and dentist about any of these concerns.

Treatment for head and neck cancers can include surgical interventions, radiation therapy and/or chemotherapy. This will depend on the size, location, and progression of the cancer, among other factors. 

Treatment may include the insertion of a breathing tube (tracheostomy) or feeding tube (nasogastric or percutaneous endoscopic gastrostomy). For some these are temporary measures while recovering from surgery, for others they can be life-long changes. 

Breathing tubes impact and change the person’s ability to speak, cough and swallow. Feeding tubes can support the person’s nutritional needs. Changes to communication and swallowing may mean the person has difficulty with everyday activities such as eating a meal with family and singing their favourite songs. 

Survivorship is high, meaning people are living longer with the impacts of their cancer and its treatment. In 2006–2010, the five-year relative survival was 68% for all head and neck cancers combined.

What are the lasting effects?

Living with head and neck cancer may have big impacts on the physical, emotional, and social wellbeing of the person and their family.

At various stages of recovery, people who have had head and neck cancer can experience life-altering consequences, including pain and difficulties speaking, eating, drinking, swallowing and breathing. Their appearance may change after oral or facial reconstruction.

Older woman holds her throat
The cancer and its treatment can have major impacts on quality of life. Shutterstock

Survivors experience varying degrees of disease severity and feelings of distress. One survivor described her experience of head and neck cancer as “brutal,” saying “we lose our careers […] our relationships fall apart.” 

Examining social media posts on #headandneckcancer highlights others are concerned about fatigue, appearance, weight and nutrition. 

Families also feel the impact, with many experiencing elevated levels of distress and reduced quality of life.

Reducing stigma

Some of the risk factors for head and neck cancers such as smoking and heavy drinking are seen as “lifestyle risk factors” and may attract stigma. This can have a significant impact on recovery. 

Stigma increases distress, depression, anxiety and reduces social participation. These impacts are exacerbated for those who live in the public eye or are professional voice-users such as singers, radio broadcasters or teachers.


Read more: ‘It’s your fault you got cancer’: the blame game that doesn’t help anyone


Supporting loved ones after head and neck cancer

People with head and neck cancers require specialist, interdisciplinary health care. Multidisciplinary care teams include medical, nursing, and allied health professionals (speech pathologists, physiotherapists, dietitians, and occupational therapists) who work collaboratively to optimise the person’s health and rehabilitation

Original Article

Survivors also need strong social support, as changes in facial appearance and difficulties speaking and eating can lead to feelings of isolation, frustration, and a loss of enjoyment in social situations. Seeking psychological and emotional support is invaluable.

When communicating with a person with head and neck cancer, allow extra time for them to speak, maintain eye contact, minimise background noise and use body language and gesture to convey messages. 

Farnham’s family acknowledge a “long road of recovery and healing”. We wish our much-loved Farnsey a pathway through cancer that is enriched with love and support of family, friends, community and music.

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Diagnose HPV-driven oropharyngeal cancer

Accuracy of high-risk HPV DNA PCR, p16(INK4a)immunohistochemistry or the combination of both to diagnose HPV-driven oropharyngeal cancer

Original Article

Abstract

Background

The incidence of high-risk human papillomavirus (hrHPV)-driven head and neck squamous cell carcinoma, in particular oropharyngeal cancers (OPC), is increasing in high-resource countries. Patients with HPV-induced cancer respond better to treatment and consequently have lower case-fatality rates than patients with HPV-unrelated OPC. These considerations highlight the importance of reliable and accurate markers to diagnose truly HPV-induced OPC.

Methods

The accuracy of three possible test strategies, i.e. (a) hrHPV DNA PCR (DNA), (b) p16(INK4a)immunohistochemistry (IHC) (p16), and (c) the combination of both tests (considering joint DNA and p16 positivity as positivity criterion), was analysed in tissue samples from 99 Belgian OPC patients enrolled in the HPV-AHEAD study. Presence of HPV E6*I mRNA (mRNA) was considered as the reference, indicating HPV etiology.

Results

Ninety-nine OPC patients were included, for which the positivity rates were 36.4%, 34.0% and 28.9% for DNA, p16 and mRNA, respectively. Ninety-five OPC patients had valid test results for all three tests (DNA, p16 and mRNA). Using mRNA status as the reference, DNA testing showed 100% (28/28) sensitivity, and 92.5% (62/67) specificity for the detection of HPV-driven cancer. p16 was 96.4% (27/28) sensitive and equally specific (92.5%; 62/67). The sensitivity and specificity of combined p16 + DNA testing was 96.4% (27/28) and 97.0% (65/67), respectively. In this series, p16 alone and combined p16 + DNA missed 1 in 28 HPV driven cancers, but p16 alone misclassified 5 in 67 non-HPV driven as positive, whereas combined testing would misclassify only 2 in 67.

Conclusions

Single hrHPV DNA PCR and p16(INK4a) IHC are highly sensitive but less specific than using combined testing to diagnose HPV-driven OPC patients. Disease prognostication can be encouraged based on this combined test result.

Peer Review reports

Background

In high-resource countries, human papillomavirus (HPV)-driven head and neck squamous cell carcinoma represents an increasing health problem, particularly in cancers of the oropharyngeal region, including base of tongue and tonsils [1,2,3,4]. An estimated 20–40% of oropharyngeal cancers (OPC) is believed to be caused by HPV infection, and the large majority of them (> 80%) are due to HPV16 [25]. Patients with HPV-induced cancers respond better to treatment and consequently have better survival than patients with HPV-unrelated OPC [6,7,8,9,10,11]. HPV-positive tumours, compared to the HPV-negative ones, are characterized by multiple molecular and clinic-pathological differences [12], which should be further investigated. These considerations highlight the importance of reliable and accurate markers, or marker combinations, to diagnose truly HPV-induced OPC and guiding patients’ risk-stratification.

The most widely applied detection method was based on PCR amplification of viral DNA to determine HPV-positivity. However, several independent studies have highlighted that PCR-based assays for the detection of HPV DNA are not sufficiently accurate to establish the viral causality [13,14,15,16,17]. These PCR-based methods are highly sensitive and can detect even a few DNA copies per sample, which might yield false-positive results mainly reflecting transient infections [18,19,20]. Additional markers, such as the presence of viral E6/E7 mRNA transcripts and p16(INK4a) expression as surrogates for HPV-induced transformation, allow a more accurate classification of HPV-driven head and neck cancers (HNC) [1521,22,23,24,25].

Nowadays, HPV E6/E7 oncogene transcript detection is considered the gold standard, for HPV-induced malignancies particularly depend on the carcinogenic potential of the HPV E6 and E7 oncoproteins [2326]. Nevertheless, viral transcript detection is laborious and may not be feasible everywhere in daily lab routine. This is particularly true for the detection of mRNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissue specimens, which are commonly used during routine diagnostic work up; however, RNA integrity may be affected by the fixation protocol.

HPV E7 oncogenic signaling brings about substantial overexpression of the cellular protein p16(INK4a) in HPV-transformed cells [27]. Therefore, the immunohistochemical detection of p16(INK4a) overexpression is presently applied as a surrogate biomarker of HPV-transformed cervical epithelium [28,29,30]. Similarly, p16(INK4a) immunohistochemistry (IHC) is regularly used to establish HPV association in HNC [222331,32,33]. Apart from single p16(INK4a) IHC, combined p16(INK4a) and HPV DNA detection by PCR is oftenly used.

HPV-AHEAD (FP7 funded network)

The HPV-AHEAD study (“Role of human papillomavirus infection and other co-factors in the aetiology of head and neck cancer in Europe and India”) group comprised partners from six European countries and from India (website HPV-AHEAD: https://hpv-ahead.iarc.fr/). The main goal of the study was to perform a comprehensive analysis on a large number of HNC cases to clarify pathogenic pathways in HNC carcinogenesis, and to identify clinically useful biomarkers.

In a previous publication [34], the results of the histological and molecular assessment of 1039 archived HNC specimens from Belgian patients were described, primarily using the detection of HPV DNA, mRNA, and p16(INK4a) IHC. In this study, we focus on the accuracy of these tests—individually and in combination—to diagnose hrHPV-driven oropharyngeal cancer.

Methods

Patient selection, clinical information and tissue specimen collection for the Belgian cohort

The overall study included patients with oropharyngeal, oral cavity, laryngeal, hypopharyngeal, and unspecified head and neck squamous cell carcinoma. For a detailed description of the patient characteristics, we refer to the previous publication of the Belgian HPV-AHEAD study data [34]. For the analyses in this study, the focus was on the oropharyngeal cancers [ICD-O-3 codes: C01 (base of tongue); C02.4 (lingual tonsil); C05.1 (soft palate); C05.2 (uvula); C09 (tonsil): C09.0, C09.1, C09.8 and C09.9; C10 (oropharynx): C10.0–10.4, C10.8 and C10.9].

FFPE tumour blocks and clinical information were collected from OPC patients treated in two Belgian hospitals (GZA and UZA), diagnosed between 1980 and 2010.

Ethical clearance was obtained from the Ethical Committees of ‘GZA hospitals’ (ref nb: BVDE/hp/2013/01.147), ‘UZA & UA (University of Antwerp)’ (ref nb: 11/47/362) and IARC, Lyon, France (ref nb: 11–30).

Preparation of tissue sections (University of Antwerp, Antwerp, Belgium)

FFPE-tissue blocks were all processed at the UA laboratory of cell biology and histology, following the optimized HPV-AHEAD sectioning protocol [3435]. Briefly, minimal ten sections (S) were prepared from each FFPE block. The first (S1) and the last (S10) 5 µm sections were hematoxylin and eosin (H&E) stained for morphologic histology interpretation and used to check for the presence of tumour. S2 and S9 (5 µm) were used for p16(INK4a) IHC staining, while the 10 µm sections S3–5 and S6–8 were used for the extraction of RNA and DNA, respectively.

Histological review

All sections were re-evaluated by the HPV-AHEAD pathology review panel. The review was blinded with respect to the original local diagnosis. Only FFPE blocks where S1 and S10 H&E sections reflected squamous tumour tissue were included in the analysis [34].

HPV E6*I mRNA analysis (DKFZ, Heidelberg, Germany)

All OPC cases were analysed for the presence of: (i) HPV16 E6*I mRNA, and (ii) ubiquitin C (ubC) mRNA as a cellular mRNA positive control (housekeeping gene used for RNA quality control). OPC cases positive for DNA of a non-HPV16 genotype were additionally analysed for E6*I mRNA of the respective genotype. Specimens that were HPV E6*I and/or ubC mRNA-positive (RNA+) were considered RNA valid. Reverse Transcription-PCR was carried out using the QuantiTect Virus Kit (Qiagen, Hilden, Germany), as described in full in former HPV-AHEAD publications [3436]. The type-specific E6*I mRNA assays identifying transcripts of fourteen high-risk and six possible/probable high-risk HPV genotypes [37] were applied.

HPV DNA genotyping (IARC, Lyon, France)

HPV DNA genotypes were detected by a E7 type-specific multiplex genotyping (E7-MPG) assay, which combines multiplex PCR and bead-based Luminex technology (Luminex Corporation, Austin, TX), as previously described [3839]. Type specific-MPG uses HPV type-specific primers targeting the E7 region of thirteen high-risk and six possible/probable high-risk HPV genotypes (HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68a and b, 70, 73 and 82), as well as two low-risk HPV genotypes (HPV 6 and 11). Two primers for amplification of the beta-globin (β-globin) gene were also included to control for the DNA quality of each specimen. A detailed description of the DNA extraction and further HPV genotyping test characteristics can be found in the previous publication on the Belgian HPV-AHEAD study [34]. Genotyping controls and DNA preparation were blindly analysed, and no sign of contamination of negative controls was detected during the laboratory work.

p16(INK4a) expression (Roche mtm laboratories, Mannheim, Germany)

Expression of p16(INK4a) was evaluated by IHC, with a dual-immunostaining protocol for the simultaneous immunostaining of both p16(INK4a) and Ki-67 biomarkers (CINtec PLUS kit, Roche mtm laboratories AG, Mannheim, Germany), as previously described in the HPV-AHEAD publications [3436]. As in all HPV-AHEAD studies [343640], a continuous, diffuse staining for p16(INK4a) within the cancer area of the tissue sections was considered as positive, while a focal staining or no staining was considered negative. IHC slides were analysed without knowledge of any other clinical information (including HPV DNA and RNA status) by the scientists RR or DH and reviewed by one of the European members of the HPV-AHEAD pathology review panel (JPB, BLR, or FM). Discrepant cases were re-evaluated by a pathologist outside the review panel (AC), and final classification of the staining was based on majority consensus results.

Corresponding to the former Belgian HPV-AHEAD publication [34], the p16 slides with technical issues were restained and re-evaluated, to minimize the number of missing results.

Statistical analysis

Presence of viral mRNA was considered as the reference indicating HPV etiology. The accuracy of three possible test strategies was analysed: (a) hrHPV DNA PCR alone, (b) p16(INK4a) IHC alone, and (c) the combination of p16(INK4a) IHC and hrHPV DNA PCR; where positivity is defined by a co-positive result with both tests, a negative result by a co-negative result for both tests, and a discordant result by only one test being positive and the other being negative. Test strategy (c) involves three algorithms: ALGORITHM 1 (p16 + DNA) consists of p16(INK4a) IHC and hrHPV DNA PCR on all samples; ALGORITHM 2 (p16 → DNA) involves p16(INK4a) staining of all samples, followed by the HPV DNA test only on the p16(INK4a)-positive samples; ALGORITHM 3 (DNA → p16) involves HPV DNA PCR on all samples, followed by p16(INK4a) staining only on the HPV DNA-positive samples.

Sensitivity was defined as the proportion of test positive samples among HPV RNA-positive patients. Specificity was defined as the proportion of negative test results among HPV RNA-negative patients. Relative sensitivity and specificity of each test compared to the other tests were also assessed. Binomial 95% confidence intervals (95% CIs) were computed for proportions. Given the matched testing of the same patient specimens, McNemar 95% CIs were computed for relative accuracy parameters. Continuous variables were summarized by their mean and 95% CIs. ANOVA was used to compare mean age by gender.

Statistical analyses were performed using STATA 16 (StataCorp, College Station, TX). p-values were two sided and statistical significance was set at p equal or less than 0.05.

Results

Study population characteristics

Ninety-nine of 116 OPC patients were included in the analysis, after exclusions based on the pathology review (for reasons of not being a squamous cell carcinoma or not reflecting invasive cancer, N = 13) and beta-globin PCR negativity (N = 4). 71.7% (71/99) of the patients were male, 26.3% (26/99) were female, and for the remaining two samples the gender of the patients was not specified. The mean age at diagnosis was 67.3 years (95% CI 64.9–69.7) and was not different between males and females (p = 0.47).

HPV prevalence in OPC cases

HPV prevalence was determined by HPV DNA PCR, p16(INK4a) IHC, E6*I mRNA, and all combinations of tests in the HPV-AHEAD study. Out of 99 OPC cases, 36.4% (36/99) contained HPV DNA, 34.0% (33/97) showed p16(INK4a) positivity, and 28.9% (28/97) were HPV RNA-positive (Table 1). Twenty-six of the 28 HPV RNA-positive samples were positive for HPV16 (92.9%), the remaining 2 samples contained HPV18 (7.1%).Table 1 Prevalence of HPV determined by HPV DNA PCR (DNA), p16(INK4a)IHC (p16), E6*I mRNA (RNA), and all combinations of tests, in oropharyngeal cancer

Full size table

The proportion of HPV-positive OPCs varied between 28.4% (27/95) and 28.9% (28/97) for all combinations of tests that included RNA testing (DNA + RNA, p16 + RNA, DNA + p16 + RNA). For the combination of testing for HPV DNA and p16(INK4a) IHC, the overall prevalence was slightly higher (30.9%, 30/97).

Absolute and relative accuracy in the oropharynx and its subsites

Both absolute and relative accuracy of hrHPV DNA detection by PCR (hrHPV DNA), p16(INK4a) IHC (p16), and combined p16(INK4a) and DNA testing algorithms (p16 + DNA, p16 → DNA and DNA → p16), to identify a transforming HPV infection were calculated. In the following tables, only the results are shown for the samples that had valid results on all three tests performed (N = 95).

All RNA-positive OPC cases were positive for hrHPV DNA (100%, 28/28), in contrast to one out of 28 HPV RNA-positive samples that did not have a positive p16(INK4a) result (3.6%). Five out of 67 RNA-negative cases showed hrHPV DNA-positivity (7.5%), the same as observed for p16(INK4a) IHC. This number would be further lowered to only 2 positive cases out of 67 RNA-negatives (3.0%), if hrHPV DNA and p16(INK4a) testing (p16 + DNA) were combined. The same holds for the other algorithms where all samples would initially be tested on p16(INK4a) (p16 → DNA) or hrHPV DNA (DNA → p16), followed by the other test if the initial test result turned out positive. Data are detailed in Table 2, for all OPC cases, and for the tonsils and the base of tongue in specific. As the number of samples from other oropharyngeal subsites was very low, no relevant data can be shown.Table 2 hrHPV DNA, p16(INK4a) (p16) and combined hrHPV DNA/p16(INK4a)test results by hrHPV RNA status in cancers of the oropharynx, tonsils and base of the tongue

Full size table

The accuracy of hrHPV DNA PCR and p16(INK4a) IHC to detect a transforming HPV infection in OPCs was calculated (Table 3). Highest sensitivity (100.0%, 28/28) was noted for hrHPV DNA testing, while specificity was equal for both hrHPV DNA and p16(INK4a) (92.5%, 62/67). The best compromise was found in the combined testing of hrHPV DNA PCR and p16(INK4a)staining, with 96.4% (27/28) sensitivity and 97.0% (65/67) specificity. When looking in more detail to the proposed algorithms, all provided equal accuracy, however, with a 60% reduction in the number of HPV DNA PCR or p16(INK4a) IHC tests needed in the sequential testing algorithms.Table 3 Absolute sensitivity and specificity of hrHPV DNA PCR (hrHPV DNA), p16(INK4a) IHC (p16) and the combined testing (p16 + DNA) to identify a HPV-driven oropharyngeal cancer

Full size table

For the subgroup of the tonsils, p16(INK4a) staining alone was as sensitive (94.7%, 18/19) and specific (91.3%, 21/23) as the combined testing, in contrast to the base of tongue group, where all tests were 100% sensitive and specific, except for the p16(INK4a) specificity (85.7%, 12/14).

hrHPV DNA PCR testing was slightly more sensitive compared to p16(INK4a) IHC (ratio: 1.04, 95% CI 0.97–1.11), but equally specific (ratio: 1.00, 95% CI not computable) (see Table 4 and Additional file 1: Table S1). The combination of hrHPV DNA and p16(INK4a) was slightly more specific (ratio: 1.05, 95% CI 0.97–1.21) compared to both single tests.Table 4 Relative sensitivity and specificity of hrHPV DNA PCR (DNA) vs p16(INK4a) IHC (p16), and of DNA and p16(INK4a) vs combined testing (p16 + DNA), to identify a HPV-driven oropharyngeal cancer

Full size table

Discussion

In these Belgian OPC patients, PCR testing for HPV DNA showed 36% positive cases. This proportion lies somewhere between other published results from different parts of the world. Castellsagué et al. found a considerably lower prevalence of HPV DNA: 24.9% in OPC, in a large international series of 3,680 HNC biopsies [33]. A very similar proportion of HPV DNA-positive oropharyngeal squamous cell carcinoma of 35.6% was found by Kreimer et al. [19]. However, the meta-analysis of Ndiaye et al. showed a substantially higher prevalence up to 45.8% in OPC [17]. This worldwide overall prevalence is largely influenced by the very high prevalence in North America (60.4%), while the overall prevalence in Europe lands at 41.4%. The differences can probably be explained, in part, by the differences in the geographic origin of the samples, as well as the high heterogeneity in laboratory procedures and assays used in the various studies.

Due to its high sensitivity, HPV DNA PCR-based assays can detect low viral copy numbers, which may not trigger carcinogenesis. These assays cannot distinguish between transcriptionally-active and passenger HPV infections. Therefore, other assays (HPV E6*I mRNA, and p16(INK4a) staining) were evaluated to assess whether combined testing could improve the specificity. Only 28% of the samples with a valid HPV E6*I mRNA result were positive for HPV DNA and p16(INK4a), which might be the fraction of oropharyngeal cancers caused by HPV. After all, the detection of HPV E6 and/or E7 mRNA is seen as the gold standard in this context, because HPV-driven carcinomas critically depend on the continuous expression of E6/E7 oncogenes of hrHPVs [232641]. However, the detection of viral transcripts is challenging, not only because the RNA extraction step is laborious and time consuming, but specific infrastructures and equipment are needed. Therefore, HPV RNA assays may not be routinely feasible in all laboratories or on all tissue samples.

HPV-driven OPC represents an increasing health problem, and therefore, reliable and accurate diagnosis becomes essential. In our Belgian HPV-AHEAD study, HPV DNA PCR testing alone was 100% sensitive, but less specific (92.5%) compared to mRNA testing. The inherent strength of the PCR-based methodology lies in its capacity to detect very small amounts of HPV DNA. At the same time, strict laboratory procedures and controls are critical in reducing contamination-related false-positive findings [42]. Immunohistochemistry for p16(INK4a) is most widely used as a surrogate marker for hrHPV infection in FFPE tissues, also for oropharyngeal squamous cell carcinoma. p16(INK4a) IHC testing alone was a bit less sensitive (96.4%), but co-presence of hrHPV DNA and p16(INK4a) positivity was similarly sensitive (96.4%) and more specific (97.0%) compared to each test separately. In literature, several authors have advocated against the use of either p16(INK4a) or hrHPV DNA alone as indicators of HPV-induced etiology in cancers, but recommended their combined use as a reliable and practical approach to differentiate HPV-induced from HPV-unrelated tumours [2643,44,45]. The meta-analysis performed by Prigge et al. [46] also showed a similarly high (pooled) sensitivity of the combined testing (93%) and either p16(INK4a) (94%) or HPV DNA (98%) alone, and the (pooled) specificity (96%) was significantly higher than either testing method alone (83% and 84%, respectively). These accuracy data were confirmed by these Belgian results.

Relative sensitivities and specificities were not significantly different from unity in our study, nor in the meta-analysis of Prigge et al. [46], where significance was only reached for the relative specificity of the combination of HPV DNA PCR and p16(INK4a) tests versus p16(INK4a)IHC [rel. spec.: 1.13 (95% CI 1.04–1.23)], by pooling from multiple studies.

Furthermore, better clinical outcomes have been reported for patients with HPV-induced compared to HPV-unrelated OPC [6,7,8,9,10,11]. HPV-positive OPC patients show better age-standardised survival than HPV-negative counterparts, leading to investigation of de-intensified therapies to improve their quality of life. However, recent trials have shown worse survival outcomes [47,48,49]. Therefore, it is crucial to further characterize the molecular mechanisms defining HPV-driven OPC in order to identify novel prognostic markers and, in a more distant future, probable targets for more tailored and effective therapies for this subtype of OPC patients, with a therapeutic success at least equal or improved compared to current treatment regimens.

Improved prognostication by combined p16(INK4a) and hrHPV DNA detection compared to single marker analysis has been demonstrated in a large meta-analysis on tumours in the head and neck region [50]. In our study, 97% (92/95) of the patients would have been correctly diagnosed with the combined testing approach. However, one 58-year old male (current smoker and alcohol consumer) with a T1 (N0 M0) microinvasive tonsillar tumour might have been considered spuriously as having a bad prognosis by applying this combined test strategy, as his tumour would have been classified as a HPV-unrelated case, being p16(INK4a) negative while actually both DNA and mRNA HPV16 positive. More than six years after diagnosis, the patient was alive without any evidence of disease.

On the other hand, disease-specific survival rates are not improved among HPV DNA-positives where HPV is not the cause of carcinogenesis. In our series of 95 Belgian OPC patients, the number of false positive cancers would be reduced from five to two with the combined p16 + DNA detection. The two HPV-unrelated cancer patients were male and diagnosed with a tonsillar cancer. The first patient, with a Tx N2 M1 tonsil NOS tumour, was a heavy drinker and current smoker who only underwent surgery and had a recurrence within 6 months. He died 2 years after being diagnosed. The other patient, with a T3 N2 tonsil NOS tumour, received surgery followed by radiotherapy and concurrent chemotherapy for 2 months. At the last follow-up date, this patient was alive, but with evidence of residual disease. Of note, these two HPV-unrelated patients clearly had a much worse disease status at diagnosis and thereby reduced survival chances compared to the above described HPV-driven tonsillar cancer patient.

Ninety-seven percent of the OPC patients in our study would have been correctly diagnosed as patients with a HPV-driven cancer by combined p16(INK4a) and hrHPV DNA (p16 + DNA) detection. Sequential testing algorithms (p16 → DNA and DNA → p16) resulted in equally accurate results, however, with a 60% reduction in the number of tests needed to be performed. This will cause a substantial reduction in costs and laboratory time, while providing the same clinical value. Especially the algorithm of p16(INK4a) on all samples followed by HPV DNA PCR on p16(INK4a)-positive samples only would be a practical strategy. After all, p16(INK4a) IHC can easily be combined with standard histology when a H&E-stained tissue section is prepared for examination by a pathologist. It is a routine diagnostic procedure, at a relatively low cost, available as a validated in-vitro diagnostic reagent and a fully automated protocol, which generates results within several hours after the procedure has been requested. HPV DNA PCR is also a standard laboratory procedure with high throughput and quick results, although against a higher cost. Preselection by p16(INK4a)-staining therefore reduces the workload and associated costs, and the combination of HPV DNA and p16(INK4a)testing leads to an important reduction of the number of false-positive observations versus the use of either of these assays alone.

Limitations

The limited number of OPC cases and the respective anatomical subsites present in this cohort could have influenced the precision of the accuracy. However, more studies will emerge from the HPV-AHEAD consortium and a new updated meta-analysis on diagnostic accuracy of p16(INK4a) immunohistochemistry in oropharyngeal squamous cell carcinomas is planned (which will include all studies from the meta-analysis by Prigge et al. [46], several HPV-AHEAD datasets and studies identified from the literature published after the meta-analysis of Prigge). A fine anatomical sub-classification can be incorporated as covariate, which hopefully yields statistical power.

Conclusions

In conclusion, combined testing for hrHPV DNA and p16(INK4a) enhances specificity up to 97%, while maintaining high sensitivity (96%), compared to single testing. The diagnostic test combination represents an accurate and accessible testing strategy in the clinical setting for diagnosis of HPV-induced OPC (especially for base of tongue and tonsillar cancers), allowing discriminant prognostication.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CI:

Confidence intervalFFPE:

Formalin-fixed, paraffin-embeddedH&E:

Hematoxylin and eosinHNC:

Head and neck cancersHPV:

Human papillomavirushrHPV:

High-risk human papillomavirusIHC:

ImmunohistochemistryOPC:

Oropharyngeal cancerp16:

p16(INK4a)PCR:

Polymerase chain reactionRNA+:

mRNA-positiveS:

SectionubC:

Ubiquitin C

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Acknowledgements

We are very grateful for the excellent work performed by Sofie Thys (University of Antwerp, Laboratory of cell biology and histology), for her meticulous work in preparing FFPE slide sections and logistical coordination and support of the study. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.

‘HPV-AHEAD study group’: Christine Carreira3, Sandrine McKay-Chopin3, Rudrapatna S. Jayshree12, Kortikere S. Sabitha12, Ashok M. Shenoy12, Alfredo Zito14, Fausto Chiesa15, Marta Tagliabue15, Mohssen Ansarin15, Subha Sankaran17, Christel Herold-Mende21,22, Gerhard Dyckhoff22, George Mosialos23, Heiner Boeing24, Xavier Castellsagué25†, Silvia de Sanjosé25, Marisa Mena25, Francesc Xavier Bosch25, Laia Alemany25, Pulikottil Okkuru Esmy26, Manavalan Vijayakumar27, Aruna S. Chiwate28, Ranjit V. Thorat28, Girish G. Hublikar28, Shashikant S. Lakshetti28, Bhagwan M. Nene28, Amal Ch Kataki29, Ashok Kumar Das29, Kunnambath Ramadas30, Thara Somanathan30

3Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer (IARC); Lyon; France; 12Kidwai Memorial Institute of Oncology; Bangalore, Karnataka; India; 14IRCCS Istituto Tumori “Giovanni Paolo II”; Bari; Italy; 15Division of Pathology, IEO, European Institute of Oncology IRCCS; Milan; Italy; 17Rajiv Gandhi Centre for Biotechnology; Poojappura, Thiruvananthapuram, Kerala; India; 21Department of Neurosurgery, Head and Neck Surgery, University of Heidelberg; Germany; 22Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg; Germany; 23Aristotle University of Thessaloniki; Greece; 24German Institute of Human Nutrition; Berlin; Germany; 25Catalan Institute of Oncology, IDIBELL, L’Hospitalet de Llobregat; Spain; 26Christian Fellowship Community Health Centre; Ambillikai; India; 27YEN ONCO Centre, Yenepoya University, Deralakatte, Mangalore 575018: Karnataka; India; 28Nargis Dutt Memorial Cancer Hospital; Barshi; India; 29Dr B. Borooah Cancer Institute, Guwahati; Assam; India; 30Regional Cancer Centre; Thiruvananthapuram; India. Dr. Castellsagué passed away on June 12th, 2016.

Funding

The global HPV-AHEAD study was initially funded by the European Commission, with Grant Number: FP7-HEALTH-2011-282562. Sciensano, the employer of CS and MA, received funding for the analysis of the Belgian part of the HPV-AHEAD study, in part, by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. MA was also supported by the Horizon 2020 Framework Programme for Research and Innovation of the European Commission, through the RISCC Network (Grant No. 847845); and the Belgian Foundation Against Cancer through the IHUVACC project.

Author information

Authors and Affiliations

  1. Unit of Cancer Epidemiology, Belgian Cancer Centre, Sciensano, Juliette Wytsmanstraat 14, 1050, Brussels, BelgiumCindy Simoens & Marc Arbyn
  2. AMBIOR, Laboratory for Cell Biology & Histology, University of Antwerp, Antwerp, BelgiumCindy Simoens, Ivana Gorbaslieva & Johannes Bogers
  3. Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer (IARC), Lyon, FranceTarik Gheit, Eric Lucas, Massimo Tommasino, Christine Carreira & Sandrine McKay-Chopin
  4. Roche Diagnostics GmbH, Mannheim, GermanyRuediger Ridder & Susanne Rehm
  5. Ventana Medical Systems, Inc. (Roche Diagnostics Solutions), Tucson, AZ, USARuediger Ridder
  6. Infections and Cancer Epidemiology, Research Program Infection, Inflammation and Cancer, Deutsches Krebsforschungszentrum, Heidelberg, GermanyDana Holzinger & Michael Pawlita
  7. Laboratory for Pathological Anatomy, Sint Augustinus Hospital, GZA, Antwerp, BelgiumPeter Vermeulen
  8. Department of Pathology, Antwerp University Hospital, Edegem, BelgiumMartin Lammens
  9. Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, BelgiumMartin Lammens
  10. Department of Otorhinolaryngology, Head and Neck Surgery, Antwerp University Hospital, Edegem, BelgiumOlivier M. Vanderveken
  11. Department of Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, BelgiumOlivier M. Vanderveken
  12. Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, 560029, IndiaRekha Vijay Kumar
  13. Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha, Maharashtra State, 442102, IndiaNitin Gangane
  14. IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, ItalyAlessandro Caniglia
  15. Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, ItalyFausto Maffini
  16. Hospital del Mar, Parc de Salut Mar, Pg/Marítim 25-29, 08003, Barcelona, SpainMaria Belén Lloveras Rubio
  17. Rajiv Gandhi Centre for Biotechnology, Poojappura, Thiruvananthapuram, Kerala, 695014, IndiaDevasena Anantharaman & Madhavan Radhakrishna Pillai
  18. Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, ItalySusanna Chiocca
  19. Genomic Epidemiology Branch, International Agency for Research On Cancer (IARC), Lyon, FrancePaul Brennan
  20. Research Triangle Institute (RTI) International India, New Delhi, IndiaRengaswamy Sankaranarayanan

Consortia

the HPV-AHEAD study group

  • Christine Carreira
  • , Sandrine McKay-Chopin
  • , Rudrapatna S. Jayshree
  • , Kortikere S. Sabitha
  • , Ashok M. Shenoy
  • , Alfredo Zito
  • , Fausto Chiesa
  • , Marta Tagliabue
  • , Mohssen Ansarin
  • , Subha Sankaran
  • , Christel Herold-Mende
  • , Gerhard Dyckhoff
  • , George Mosialos
  • , Heiner Boeing
  • , Xavier Castellsagué
  • , Silvia de Sanjosé
  • , Marisa Mena
  • , Francesc Xavier Bosch
  • , Laia Alemany
  • , Pulikottil Okkuru Esmy
  • , Manavalan Vijayakumar
  • , Aruna S. Chiwate
  • , Ranjit V. Thorat
  • , Girish G. Hublikar
  • , Shashikant S. Lakshetti
  • , Bhagwan M. Nene
  • , Amal Ch. Kataki
  • , Ashok Kumar Das
  • , Kunnambath Ramadas
  •  & Thara Somanathan

Contributions

CS, MA and JB designed the Belgian part of the HPV-AHEAD study; CS and MA performed the statistical analysis and interpreted the findings; CS also compiled the database, managed the Belgian part of the project and wrote the manuscript. IG collected all patient samples and the corresponding clinical information; PV, ML and OMV facilitated and supervised the specimen and clinical data collection. TG, DH, SR, AC, DA, and PB performed the respective DNA, RNA or p16 tests, and interpreted the data; they were supervised by MT, MP, RR, and MRP. RVK, NG, FM, BMLR, and JB were responsible for the histological review of all specimens. EL managed the overall HPV-AHEAD database, and validated the data entry. MT, RS, MP, MA, JB, SC, and RR were the PI’s of the HPV-AHEAD study and therefore responsible for the largest funding acquisition. TG, RR, IG, EL, FM, SC, JB, MT, and MA reviewed and/or edited the manuscript. All co-authors approved the final manuscript and its submission to this journal.

Corresponding authors

Correspondence to Cindy Simoens or Marc Arbyn.

Ethics declarations

Ethics approval and consent to participate

All methods were carried out in accordance with relevant guidelines and regulations. Ethical clearance was obtained from the Ethical Committees of ‘GZA hospitals’ (ref nb: BVDE/hp/2013/01.147), ‘UZA & UA (University of Antwerp)’ (ref nb: 11/47/362) and IARC, Lyon, France (ref nb: 11–30). Informed consent of the individual patient was not necessary, as it concerns biobank-based research. The ethical principles, detailed by a European network specialized in biobanking (Hansson MG, Methods Mol.Biol 2011; 675:39–59), are respected. The need of informed consent was waived by the Ethical Committees of ‘GZA hospitals’ and ‘UZA & UA (University of Antwerp)’ for the Belgian patients.

Consent for publication

Not applicable.

Competing interests

RR and SR are employees of Roche. All other authors declare that they have no competing interests.

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World head and neck cancer day

Three health organisations are reminding Kiwis that head and neck cancer can be prevented.

With Wednesday marking World Head and Neck Cancer Day, the health agencies say it’s a timely opportunity to raise awareness about the devastating health impacts of head and neck cancers, including oropharyngeal – throat – cancer caused by Human Papillomavirus Virus – HPV.

Original Article

The Head and Neck Cancer Foundation Aotearoa (HNCFA), the Head and Neck Cancer Support Network (HNCSN) and the Sexually Transmitted Infections Education Foundation (STIEF) is also reminding New Zealanders that prevention is available for free in the form of the Gardasil vaccine.

This highly effective and safe vaccine prevents infection with HPV, and significantly reduces the risk of developing many different forms of cancer, including oropharyngeal cancer, cervical cancer and penile cancer.

This year, it is even more important because a significant proportion of our children have been missing out on this health prevention opportunity, due to the disruption brought by Covid-19, which is of great concern, say the health organisations.

In 2021, 53,000 fewer vaccines were delivered than in 2019, and the total reduction in doses over two years has been approximately 78,000 – that’s more than 30,000 children who have missed out.

“It was a no-brainer to vaccinate my children against HPV – they are all fully vaccinated with Gardasil. Knowing that they are protected from HPV-related cancers is one less worry on my mind,” says HPV head and neck cancer survivor, Doug Russell.

“As a parent I do not want to be in a position later in life when our children could come to us with HPV and ask why they did not get vaccinated for this entirely preventable disease.”

HPV is one of the world’s most widespread viral infections, usually resulting from direct skin-to-skin contact during intimate sexual contact with someone who has HPV. Without immunisation, around 80 per cent of people who have ever had penetrative, or non-penetrative sexual (vaginal, oral, or anal) contact will be infected by at least one type of HPV at some point in their lives. Unfortunately, condom use during sex doesn’t reliably prevent transmission of this virus.

Although there are over 150 types of HPV, only a small number of these are ‘high-risk HPV’ strains that have the potential to lead to cancerous changes in cells.

HPV is a bit of an “unlucky dip” really: in many people, HPV is naturally cleared by the body’s immune system, some people will retain the virus but have low-risk strains that may lead to genital warts, whilst others may have the high-risk strains and develop devastating cancers –  sometimes decades later – having never known about the original infection.

It isn’t possible to predict which group your child will fall into if/when exposed to HPV, but it is possible to protect them by getting them vaccinated, says the health agencies.

The virus is most commonly associated with cervical cancer, but can also cause other cancers in the genital area of people of all genders, specifically the vagina, vulva, penis, and anus.

In recent years, medical professionals have also observed a rapid rise in HPV-related oropharyngeal cancer in heterosexual people who are otherwise healthy. For this group, the main risk is oropharyngeal cancer, which affects the throat (tonsils, base of tongue and soft palate).

Although this type of cancer has traditionally been linked to smoking and heavy drinking, in recent years HPV has become the leading cause. Oropharyngeal cancers caused by HPV are rapidly rising in developed countries. In New Zealand, 95 new cases of HPV-related oropharyngeal cancer with 25 deaths were estimated for 2018. In 2020, there were 334 oropharyngeal cancer cases caused by HPV.

Doug Russell, an otherwise healthy 58-year-old, describes the lead-up to “the single toughest day” of his life in 2017.

“I had a shave one lazy Sunday morning and there was nothing wrong with me. And at lunchtime, I was sitting in the kitchen having a sandwich, and I put my hand on my throat and I said to my wife Sarah “what is that lump?”

And there was a big lump.

“So on Monday, I went to the doctor and that started this whole thing, it just appeared overnight like that.”

Doug was infected with a high-risk strain of HPV, which he had never been aware of until it led to his cancer.

“I thought I was living my life to the fullest, and I thought cancer was something that happened to other people. I really struggled, and still do struggle a little bit, to understand why this happened to me, and what the implications would be for my family.”

Doug’s experience of it happening ‘overnight’ is not uncommon. Head and neck cancers including oropharyngeal cancer are notoriously difficult to detect and, as a consequence, are often only discovered in advanced stages. Symptoms will often be very mild initially and will depend on where exactly the cancer is situated, how big it is and how far it has spread in the body.

The most common symptoms are:

•    a painless lump in the neck or in front of the ear
•    a lump or ulcer in the mouth, such as the tongue, gum, or inside the cheek
•    a persistent white or red patch in the mouth
•    a one-sided sore throat which may be associated with earache
•    pain or difficulty with swallowing
•    a hoarse voice, especially in a smoker
•    difficult or noisy breathing
•    a lump or sore on the face
•    numbness or weakness on one side of the face
•    one-sided blocked nose with bleeding
 
Many less serious conditions, apart from cancer, can cause these symptoms, but it is important to consult your doctor if they persist for more than three weeks.

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The Case for Having Dentists on Your Cancer Care Team

Caring for your oral health before, during, and after cancer treatment—a growing focus at NYU College of Dentistry—can minimize complications. Consider Dentists as apart of your Cancer Care.

Cancer treatment often takes a team of health professionals—oncologists, nurses, surgeons, radiologists, pathologists, and social workers—to coordinate and provide comprehensive support for patients. At NYU, dentists are increasingly being considered an important part of the cancer care team.  

Original Article

When faced with a cancer diagnosis, many patients push other health care to the side to focus on addressing the disease. But people with cancer can experience unique issues related to their oral health. For instance, radiation to the head and neck can damage the salivary glands, hurting their ability to produce saliva, which can lead to tooth decay or cavities. Radiation and chemotherapy can also cause painful mouth sores. Patients with cancer that has spread to their bones, or who are undergoing treatment that can weaken their bones, may be prescribed high doses of antiresorptive medications such as bisphosphonates. These medications can cause a rare condition called osteonecrosis of the jaw, in which the jawbone is exposed through the gums.  

Other treatments—including chemotherapy and bone marrow transplants—lower the immune system, leaving patients susceptible to infection. Infections in the mouth during cancer treatment are especially dangerous, given the immune system’s inability to fight back.

“An abscessed tooth may mean having to stop chemotherapy to treat the infection,” says Denise Trochesset, clinical professor and chair of the Department of Oral and Maxillofacial Pathology, Radiology and Medicine at NYU College of Dentistry.  

“Fortunately, intervening early to eliminate infection can minimize complications during the course of therapy,” says Dalal Alhajji, clinical instructor in the Department of Oral and Maxillofacial Pathology, Radiology and Medicine at NYU College of Dentistry.

Bridging the gap between cancer care and dental care
Many cancer centers lack services and protocols related to oral health; Trochesset and Alhajji are part of a small but growing number of oral health professionals working to change this.

Dalal Alhajji, DMD, MSD

NYU Dentistry’s Dalal Alhajji, DMD, MSD

Denise Trochesset, DDS

NYU Dentistry’s Denise Trochesset, DDS

“We need to give dentists a primary role on the cancer care team,” says Alhajji, who completed a fellowship in dental oncology and now specializes in treating cancer patients.

Over the past few years, NYU College of Dentistry has strengthened its connections with cancer providers at NYU Langone’s Perlmutter Cancer Center, particularly those treating head and neck cancers and diseases requiring bone marrow transplants. A growing number of patients with certain cancers are referred to the College of Dentistry for an exam prior to starting treatment. They’re seen at the NYU Dentistry Oral Health Center for People with Disabilities, where Alhajji oversees their care.

“We might not think of cancer patients as having a disability, but they may be medically disabled, even if for just a short period of time,” explains Trochesset.

During an exam and cleaning, Alhajji and dental students check for any signs of infection or other issues that could complicate cancer care. After the initial exam, patients can either return to their regular dentist or continue their care at the Oral Health Center for People with Disabilities, where general dentists and specialists are under one roof.

Closing this gap in care is not only transformative for patients, but for dental students as well. Because all NYU dental students rotate through the Oral Health Center for People with Disabilities during their third and fourth years of training, they now gain experience with a patient population being treated for cancer. 

“Our dental students already learn about cancer in their oral medicine and pathology courses—but now, it’s no longer just something they read about in their textbooks, which is unique for a dental school,” says Trochesset.

What cancer patients can do to keep their mouths healthy
Keeping up your oral hygiene before, during, and after cancer treatment is critical, according to Alhajji and Trochesset. They recommend that people diagnosed with cancer take the following steps to protect their oral health:

  • Visit a dentist before you begin cancer treatment for an exam, X-rays, and cleaning. The dentist may check for infections in your mouth, which can complicate cancer care that lowers your immune system. If your dentist finds an infection, they can treat it—through filling a cavity, extracting a tooth, or performing a root canal—prior to your cancer treatment.  
  • If you’ll be receiving radiation for cancer of the head or neck, Trochesset recommends asking your dentist about creating a custom mouth guard to wear during radiation treatments. A mouth guard can protect areas of your mouth from unnecessary radiation, and may be particularly useful for those with metal fillings and crowns. You may also benefit from jaw exercises or a referral to a physical therapist. 
  • Keep up your oral hygiene during cancer treatment. Alhajji recommends that you continue brushing your teeth, although you may want to switch to a very soft toothbrush. You may also need to take a break from alcohol-based mouthwash if you develop mouth sores.
  • Stay hydrated, especially if you are experiencing dry mouth.

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