CDA Journal - April 2021: Head and Neck Cancers and the Dental Profession by California Dental Association

Journa C A L I F O R N I A

D E N TA L

April 2021 Oral Cancer and Racial Disparity Early Detection Potentially Malignant Disorders Oral Complications

A S S O C I AT I O N

HEAD AND NECK cancers and the dental profession

Alessandro Villa, DDS, PhD, MPH

A P R I L 2021

Vol 49 Nº 4

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April 2021

C D A J O U R N A L , V O L 4 9 , Nº 4

d e pa r t m e n t s

199 The Editor/Sad or Mad: Fear and Loss of Control in the Pandemic 201 Impressions 269

RM Matters/Handling Conflicts With Confidence: Tools To Reduce Tension and Risk

271 Regulatory Compliance/Required Employee Training 273 Ethics/‘Free/Politically Correct’ Speech in the Dental Office 274 Tech Trends

201 f e at u r e s

205 Head and Neck Cancers and the Dental Profession An introduction to the issue. Alessandro Villa, DDS, PhD, MPH

207 Racial Disparity Among Adults With Oral Cancer Persists in the U.S. from 2000 to 2017 Highlighting racial disparities with respect to oral cancer to increase awareness is the first step in developing interventions to address these disparities. Abrar Bakhsh, DDS, and Caroline H. Shiboski, DDS, MPH, PhD

215 The Role of Dental Professionals in the Early Detection of Oral Cancer This article discusses the importance of performing oral cancer screenings as part of every comprehensive and periodic oral exam. Kyle Jones, DDS, PhD

223 A Guide for Dental Practitioners of Common Oral Potentially Malignant Disorders The goal of this review is to provide an updated and simple reference for dentists to guide them in lesion identification and diagnosis and, in some cases, treatment. Diana Wang, DDS; Shaiba Sandhu, BDS, DDS; and Sook-Bin Woo, DMD

239 Oral Complications From the Treatment of Oral Cavity and Oropharyngeal Cancers The sequelae of oral complications following treatment for OC/OP cancers is complex and often has a significant impact on patients’ quality of life. Karen He, BA; Trevor G. Hackman, MD; Siddharth Sheth, DO; Bhishamjit S. Chera, MD; and Muhammad A. Shazib, DMD CON TINUE S ON PAGE 197

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published by the California Dental Association 1201 K St., 14th Floor Sacramento, CA 95814 800.232.7645 cda.org

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D E N TA L

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Brian K. Shue, DDS, CDE Associate Editor Gayle Mathe, RDH Senior Editor

Volume 49 Number 4 April 2021

A S S O C I AT I O N

Blake Ellington Tech Trends Editor

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Alessandro Villa, DDS, PhD, MPH Guest Editor Andrea LaMattina, CDE Publications Manager Kristi Parker Johnson Senior Communications Specialist

The Journal of the California Dental Association (ISSN 1942-4396) is published monthly by the California Dental Association, 1201 K St., 14th Floor, Sacramento, CA 95814, 916.554.5950. The California Dental Association holds the copyright for all articles and artwork published herein.

Steven W. Friedrichsen, DDS, professor and dean, Western University of Health Sciences College of Dental Medicine, Pomona, Calif. Mina Habibian, DMD, MSc, PhD, associate professor of clinical dentistry, Herman Ostrow School of Dentistry of USC, Los Angeles Robert Handysides, DDS, dean and associate professor, department of endodontics, Loma Linda University School of Dentistry, Loma Linda, Calif. Bradley Henson, DDS, PhD , associate dean for research and biomedical sciences and associate professor, Western University of Health Sciences College of Dental Medicine, Pomona, Calif. Paul Krebsbach, DDS, PhD, dean and professor, section of periodontics, University of California, Los Angeles, School of Dentistry Jayanth Kumar, DDS, MPH, state dental director, Sacramento, Calif. Lucinda J. Lyon, BSDH, DDS, EdD, associate dean, oral health education, University of the Pacific, Arthur A. Dugoni School of Dentistry, San Francisco Nader A. Nadershahi, DDS, MBA, EdD, dean, University of the Pacific, Arthur A. Dugoni School of Dentistry, San Francisco Francisco Ramos-Gomez, DDS, MS, MPH, professor, section of pediatric dentistry and director, UCLA Center for Children’s Oral Health, University of California, Los Angeles, School of Dentistry Michael Reddy, DMD, DMSc, dean, University of California, San Francisco, School of Dentistry

The Journal of the California Dental Association is published under the supervision of CDA’s editorial staff. Neither the editorial staff, the editor, nor the association are responsible for any expression of opinion or statement of fact, all of which are published solely on the authority of the author whose name is indicated. The association reserves the right to illustrate, reduce, revise or reject any manuscript submitted. Articles are considered for publication on condition that they are contributed solely to the Journal of the California Dental Association. The association does not assume liability for the content of advertisements, nor do advertisements constitute endorsement or approval of advertised products or services.

Avishai Sadan, DMD, dean, Herman Ostrow School of Dentistry of USC, Los Angeles

Brian J. Swann, DDS, MPH, chief, oral health services, Cambridge Health Alliance; assistant professor, oral health policy and epidemiology, Harvard School of Dental Medicine, Boston

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Harold Slavkin, DDS, dean and professor emeritus, division of biomedical sciences, Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry of USC, Los Angeles

Richard W. Valachovic, DMD, MPH, president emeritus, American Dental Education Association, Washington, D.C.

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CON TINUED FROM PAGE 195

A D D I T I O N A L F E AT U R E S

251 The Effectiveness of Diode Laser Therapy With Scaling/Root Planing in Treating Periodontitis In this article, scaling/root planing plus diode laser therapy was compared to scaling/root planing only to treat moderate-severe (Stages II-III) chronic periodontitis. Joseph Zingale, DDS, MPS; Navid Knight, DDS; Miriam Robins, DDS, MS; Lisa Harpenau, DDS, MS, MBA, MA; William Lundergan, DDS, MA; and David Chambers, PhD, MEd, MBA

261 Top 10 Prescribed Drugs: What Do Dental Clinicians Need To Know This paper aims to summarize important pharmacological reactions of the top 10 most prescribed drugs in 2018 and dental treatment to help dentists recognize these potential interactions. Matthew Choi, BS, and Aviv Ouanounou, BSc, MSc, DDS

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Editor

C D A J O U R N A L , V O L 4 9 , Nº 4

Sad or Mad: Fear and Loss of Control in the Pandemic Kerry K. Carney, DDS, CDE

any years ago, I overheard a mother talking with her 5-year-old son (who happened to be traveling that day in a Superman outfit complete with cape). He was crying and she was asking him if he was sad or mad. It was touching to see a very young Superman at the mercy of his emotions. It was as if his emotions were as powerful and disruptive to his behavior as kryptonite is to Superman’s strength. That image stuck with me and I have posed that same question to myself on more than one occasion: Am I mad or am I sad? Emotions are so curious, so mercurial, so human. Emotions make us cry when we watch Disney’s “Dumbo.” Emotions move us to action (with or without the bolstering fuel of data and logic). Emotions are how we gauge the maturity level or the mental health status of some individuals. It has even been shown that without emotion to drive a decision, it is difficult or impossible to make simple consumer choices.1 But what do emotions have to do with the practice of dentistry? Every dentist learns fairly quickly that scientific knowledge, materials management and manual dexterity are only part of the equation that describes the practice of dentistry. Working with people (colleagues, team members and patients) can be stressful. Instead of just sitting down and “doing dentistry,” a day at the office can feel like you are negotiating your way through a minefield of emotions (not unlike the dramafest of a family holiday get-together). A recent study in the Journal of the American Dental Association (JADA) documented patient aggression in dental practices in the United States. It employed

In order to effectively relate to the people with whom we interact in the office, we have to be able to recognize and respond appropriately to the emotional drive behind some actions. a confidential online survey of 98 dentists to assess the incidence of 21 specific types of aggressive patient behaviors they had experienced. Granted, this was a tiny sample, and the fact that it was drawn from the faculty and alumni network of one school means generalizations based on assumptions from the results are not valid beyond the original sample. The study’s conclusions were as follows: Participants reported levels of physical, verbal and reputational aggression at rates comparable with those of other health care professionals in the United States and abroad. Additional research with larger representative samples of dentists in the United States is necessary to confirm these prevalence estimates. Further research should also investigate predictors and outcomes of patient aggression and prevention and intervention strategies.2 This study is a little like the headlines on tabloid magazines that we used to thumb through in pre-COVID-19 times while waiting in grocery store lines that would be unacceptably close vis a vis current COVID-19 social distancing. For example, the headline: “Skydiver Eaten by Hungry Birds” would lure us into a search for the story inside the magazine only to find that the sensational headline came from the speculation of a skydiver with a phobia of birds.

The headline of the JADA study is pretty sensational: workplace aggression against dentists. A perusal of the article and an understanding of the methodology and results show us that there is not much substance to the report. However, the title alone does start us thinking about just that: patient aggression against dentists. This article seemed to draw out “me too” stories of dentists who had experienced patient aggression. As usual, I felt this was not something that would happen in our practice. As usual, I was wrong. Within a matter of weeks, we had an occurrence. A patient was asked to follow our pretreatment protocol of plaque control and rinsing. She became abusive, raised her voice and accused the staff of trying to put her at risk for contracting COVID-19. This patient had been part of our practice for many years. I took her aside and told her that our protocols are designed in accordance with CDC guidelines and that our entire office is dedicated to protecting our patients, our staff and our community. She was reassured and cooperated after that. It seemed very clear that, in this case, the patient’s hostility was the result of fear and a feeling of loss of control. We all know this feeling. This COVID-19 year has made us all too often short-tempered, easy to anger, APRIL 2 0 2 1

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depressed and despondent. These are feelings that can make us sad and mad. In order to effectively relate to the people with whom we interact in the office, we have to be able to recognize and respond appropriately to the emotional drive behind some actions. It is too easy to respond in tone and kind to an angry outburst. If we find the root cause, then more often than not, we can address that cause, defuse the emotional eruption and prevent the disruption and emotional wreckage that would have followed. Balance can be restored, and we can get back to taking care of our patients. That tiny Superman from years ago was crying. In order to help him deal with his emotions in a positive way, his mother was trying to help him recognize the emotional state that was at the source of his tears. Was he mad or was he sad? Before we react to an emotional outburst, we need to ascertain and address the root cause of that outburst. It can be helpful to keep tabs on our own emotional motivations. In this

pandemic of fear and loss of control, when I wake up angry about something that is inconsequential (like the National Dog Show’s choice of Best of Show: the Scottish Deerhound), it helps to ask myself, “Am I mad or am I sad?” Knowing the answer to that can make it easier to get along with family, friends, co-worker team members and patients. It can free us to do what needs to be done. RE FE RE N CE S 1. Murray PN. How emotions influence what we buy: The emotional core of consumer decision-making. Psychology Today Feb. 26, 2013. www.psychologytoday.com/us/blog/ inside-the-consumer-mind/201302/how-emotions-influencewhat-we-buy. 2. Rhoades KA, et al. Patient aggression toward dentists. J Am Dent Assoc 2020 Oct;151(10):764–769. doi: 10.1016/j. adaj.2020.06.041.

The Journal welcomes letters We reserve the right to edit all communications. Letters should discuss an item published in the Journal within the last two months or matters of general interest to our readership. Letters must be no more than 500 words and cite no more than five references. No illustrations will be accepted. Letters should be submitted at editorialmanager. com/jcaldentassoc. By sending the letter, the author certifies that neither the letter nor one with substantially similar content under the writer’s authorship has been published or is being considered for publication elsewhere, and the author acknowledges and agrees that the letter and all rights with regard to the letter become the property of CDA.

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Impressions

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Periodontitis Increases Risk of Heart Attacks People with periodontitis are at higher risk of experiencing major cardiovascular events, according to new research from the Forsyth Institute and Harvard University scientists and colleagues. In a longitudinal study published recently in the Journal of Periodontology, Dr. Thomas Van Dyke, DDS, PhD, senior member of staff at Forsyth, Ahmed Tawakol, MD, of Massachusetts General Hospital, and their collaborators showed that inflammation associated with active gum disease was predictive of arterial inflammation, which can cause heart attacks, strokes and other dangerous manifestations of cardiovascular disease. While growing evidence has suggested a link between periodontal disease and cardiovascular disease, the independence of this association and the pathway remained unclear. Hence, the research team tested the hypotheses that inflammation of the periodontium predicts future cardiovascular disease independently of shared disease risk factors and that the mechanism linking the two diseases involves heightened arterial inflammation. For the study, researchers performed positron emission tomography (PET) and computer tomography (CT) scans on 304 individuals to view and quantify inflammation in the arteries and gums of each patient. In follow-up studies approximately four years later, 13 of those individuals developed major adverse cardiovascular events. A presence of periodontal inflammation was shown to be predictive of cardiovascular events, even after researchers controlled for all other risk factors, such as smoking, high blood pressure, obesity and diabetes. Importantly, researchers found that bone loss from prior periodontal disease was not associated with cardiovascular events. Patients who did not have actively inflamed gums had a lower risk of cardiovascular disease, even if those individuals had a prior history of periodontal disease as evidenced by periodontal bone loss in their CT scans. “This is very definitely related to people who have currently active inflammatory disease,” said Dr. Van Dyke, who is also the vice president of clinical and translational research at Forsyth. Researchers hypothesize that local periodontal inflammation activates and mobilizes cells signaling through bone marrow, which triggers the inflammation of arteries, leading to adverse cardiac events. While the study sample size is relatively small, Dr. Van Dyke said the observation is significant and should be studied in a much larger population. And for people with active periodontitis, seeking treatment could potentially prevent a dangerous cardiac event. “If you’re in the age zone for cardiovascular disease or have known cardiovascular disease, ignoring your periodontal disease can actually be dangerous and may increase your risk for a heart attack,” Dr. Van Dyke said. Learn more about this study in the Journal of Periodontology (2021); doi: 10.1002/JPER.19-0441. n APRIL 2 0 2 1

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3D Printing Impression Trays Saves Time, Money Tongue ulceration of a laboratory-confirmed COVID-19 patient. (Credit: Riad et al. is licensed under Creative Commons CC BY 2.0.)

‘COVID Tongue’ Linked to SARS-CoV-2 COVID-19 may be associated with geographic tongue (GT), which some patients are referring to as “COVID tongue,” according to a letter published Feb. 12 in the British Dental Journal and written by Russell Hathway, BDS, MBBCh, of the department of oral and maxillofacial surgery at Morriston Hospital in Swansea, U.K. Dental professionals should be aware of this possible link because it may be an indicator of infection with the novel coronavirus and patients may ask about it, according to the letter. GT, also known as erythema migrans, presents as harmless red patches on the top or the side of the tongue that may change size, location and shape. The possible link between GT and COVID-19 was identified by patients who submitted symptom reports to the Zoe COVID-19 Symptom Study app, which was created by doctors and scientists at Massachusetts General Hospital, the Harvard T.H. Chan School of Public Health, King’s College London, Stanford University School of Medicine and the health science company Zoe. Multiple people reported symptoms of what seem to be GT, but only two communications and its relationship to COVID-19 have been written to date about it, Dr. Hathway said. Though some members of the media have called for this tongue condition to be added to the list of COVID-19 symptoms, Dr. Hathway said it should 202 APRIL

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Clinicians can save money and time by 3D printing open impression trays for patients in need of multiple implant-supported prostheses, according to a study published in February in the Journal of Prosthetic Dentistry. A research team led by Xulan Yang, a postgraduate student in the oral implantology department at Peking University School and Hospital of Stomatology in Beijing, compared the accuracy and feasibility of using a digital dentistry technique with conventional open tray fabrication. The CAD/CAM workflow saved more than $4 per impression without sacrificing accuracy. The study included 22 partially edentulous adults visiting Peking University’s implant department from 2018 to 2019. The patients required impressions for multiple implantsupported restorations on the same arch, and the authors created both a conventional impression tray and a 3D printed tray for all patients enrolled in the study To create the 3D printed tray, a certified dental laboratory technician began by taking a scan of an abutment healing-level impression. A postgraduate dental student then designed an open tray based on the scan data and 3D printed the tray using a renewable and biodegradable material. The two trays did not significantly differ in accuracy, fit or impression quality. While the two trays had similar accuracy, the 3D printed tray bested the conventional design in the authors’ feasibility analysis. The 3D printed tray cost approximately 96% less than the conventional tray and took fewer minutes to create Based on their findings, the authors concluded that 3D printed custom open trays can be suitable for clinical application. However, they cautioned that their accuracy findings compared the 3D printed trays to the conventional ones and were not a measure of trueness. Learn more about this study in the Journal of Prosthetic Dentistry (2021); doi.org/10.1016/j.prosdent.2020.11.016. Tissue stops on the computer-designed custom tray: (a) none, (b) saddle-shaped, (c) marginalband and (d) inner marginal-band. (Credit: Deng et al. is licensed under Creative Commons CC BY 2.0.)

be done with caution. The diagnostic value of naming it a COVID-19 symptom is unknown, he noted. However, it is important to remember that evidence suggests that erythema migrans may be linked with elevated levels of the inflammatory cytokine interleukin-6 (IL-6), which is upregulated in severe COVID-19. Furthermore, angiotensin-converting enzyme 2 (ACE2)

receptor expression is higher in the tongue compared to other oral tissues, and the SARS-CoV-2 virus enters through ACE2 receptors, according to the letter. Read the letter to the editor in the British Dental Journal (2021); nature.com/ articles/s41415-021-2672-1.pdf?origin=ppub.

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Ancient Proteins Track Early Milk Drinking An international team led by researchers at the Max Planck Institute for the Science of Human History in Jena, Germany, and the National Museums of Kenya (NMK) in Nairobi, Kenya, has analyzed some of the most challenging ancient dental calculus to date. Their new study, published in Nature Communications, examines calculus from human remains in Africa, where high temperatures and

humidity were thought to interfere with protein preservation. Archaeological scientists are increasingly using proteomics to study ancient dairying and to track milk drinking in the ancient past. By extracting tiny bits of preserved proteins from ancient materials, researchers can detect proteins specific to milk and even specific to the milk of particular species.

Poll: Children’s Dental Care Disrupted by Pandemic A third of parents polled said the COVID-19 pandemic has made it difficult to get dental care for their children, according to the C.S. Mott Children’s Hospital National Poll on Children’s Health at Michigan Medicine. But some families may face greater challenges than others. The inability to get a dentist appointment during the pandemic was three times as common for children with Medicaid versus those with private dental coverage. The Mott poll, a nationally representative report, is based on responses from 1,882 parents with at least one child aged 3–18. Overall, 1 in 3 parents (32%) felt COVID-19 has made it harder to get preventive dental care for their child. Sixty percent of parents in the poll have tried to get preventive dental care for their child since the pandemic started. While some got an appointment in the usual time frame, 24% experienced a delay and 7% could not get an appointment at all. Among parents who tried to get their child in for preventive dental care, 15% of parents of children with Medicaid dental coverage reported not being able to get an appointment, compared to 4% of those with private dental insurance and 5% who had no coverage. The Mott poll report also revealed a silver lining of sorts: One in four parents described improvements in how their children are taking care of their teeth and gums at home during the pandemic. This included more frequent brushing (16%), flossing (11%), use of fluoride rinse(9%) and less drinking of sugary beverages (15%). Overall, 28% of parents said their child has made at least one positive change. Learn more about the Mott poll results at mottpoll.org.

Ancient dental calculus was prepared for analysis in a special clean-room facility at MPI-SHH. (Credit: M. Bleasdale.)

One critical reservoir where these proteins are preserved is in dental calculus. For this study, the research team analyzed dental calculus from 41 adult individuals from 13 ancient pastoralist sites excavated in Sudan and Kenya and, remarkably, retrieved milk proteins from eight of the individuals. “Some of the proteins were so well preserved, it was possible to determine what species of animal the milk had come from,” said lead author Madeleine Bleasdale, PhD. “And some of the dairy proteins were many thousands of years old, pointing to a long history of milk drinking in the continent.” The earliest milk proteins reported in the study were identified at Kadruka 21, a cemetery site in Sudan dating to roughly 6,000 years ago. In the calculus of another individual from the adjacent cemetery of Kadruka 1, dated to roughly 4,000 years ago, researchers were able to identify species-specific proteins and found that the source of the dairy had been goat’s milk. “This is the earliest direct evidence to date for the consumption of goat’s milk in Africa,” said Dr. Bleasdale. “It’s likely goats and sheep were important sources of milk for early herding communities in more arid environments.” Read more of this study in Nature Communications (2021); doi.org/ 10.1038/s41467-020-20682-3. APRIL 2 0 2 1

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Head and Neck Cancers and the Dental Profession Alessandro Villa, DDS, PhD, MPH

GUEST EDITOR Alessandro Villa, DDS, PhD, MPH, is an associate professor and chief of the Sol Silverman Oral Medicine Clinic and the program director for the oral medicine residency at the University of California, San Francisco. He is a diplomate of the American Board of Oral Medicine and a fellow of the Royal College of Surgeons of Edinburgh. Conflict of Interest Disclosure: None reported.

ancer patients have unique oral health needs and, depending on the cancer diagnosis and treatment, may be at significant risk for various oral complications. In 2021, 54,010 new cases of oral and oropharyngeal cancer are expected in the United States, leading to an estimated 10,850 deaths.1 Approximately 50% of patients receiving treatment for head and neck cancers develop some form of oral toxicity, including but not limited to mucositis, infections, dry mouth, osteoradionecrosis and dental caries.2 Treatment-related oral toxicities negatively affect patients’ quality of life and their ability to tolerate treatment, increase cancer treatment associated costs and can lead to worse prognoses.3 We invited experts in the field from prominent institutions to contribute to this collection of papers: Drs. Caroline Shiboski and Kyle Jones from the University of California, San Francisco, School of Dentistry, Dr. Ali Shazib and colleagues from the Adams School of

Dentistry at The University of North Carolina at Chapel Hill and Dr. Diana Wang and colleagues from the Harvard School of Dental Medicine. This issue on head and neck cancers includes current epidemiological data on oral cancer disparities; a guide on early detection of oral cancer and oral potentially malignant disorders; and a general overview of oral complications from cancer therapy. The severity of oral complications depends on the cancer stage and the type of treatment.3 Not only is the population of cancer patients and survivors growing, but there continues to be advancements in oncology with new agents, many of which are associated with both acute and chronic oral complications. We have learned over the years that no head and neck cancer patient population can be fully served without the presence of a dental team and oral medicine specialists. The general dentist is expected to provide comprehensive oral health care for the cancer patient before cancer treatment APRIL 2 0 2 1

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begins, during cancer therapy and after completion of treatment. Not only do dentists assist patients’ oral needs during their cancer treatment but may be the ones to diagnose oral cancer or an oral potentially malignant disorder. Oral cancers are thought to arise from premalignant lesions such as leukoplakia.4 Most leukoplakias show oral epithelial dysplasia at first biopsy, and the risk of malignant transformation is higher with increased severity of dysplasia (from mild to moderate or severe).5 Dentists play an important role in early diagnosis and detection of potentially malignant oral disorders

and oral cancer by taking a careful history, performing a thorough intraoral examination and either performing a biopsy of the lesion or referring the patient for a biopsy to establish a preliminary diagnosis. Early detection of early-stage oral cancer translates into better prognoses and clinical outcomes. Many thanks to my colleagues in oral medicine and oral pathology who have shared their time, expertise and enthusiasm to help familiarize the dental community with the head and neck cancer population. We hope you find these articles enlightening and compelling. n

RE F E RE N C E S 1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin 2021 Jan;71(1):7–33. doi: 10.3322/caac.21654. Epub 2021 Jan 12. 2. Sroussi HY, Epstein JB, Bensadoun RJ, et al. Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease and osteoradionecrosis. Cancer Med 2017 Dec;6(12):2918– 2931. doi: 10.1002/cam4.1221. Epub 2017 Oct 25. 3. Villa A, Sonis S. Toxicities associated with head and neck cancer treatment and oncology-related clinical trials. Curr Probl Cancer Sep–Dec 2016;40(5–6):244–257. doi: 10.1016/j. currproblcancer.2016.06.001. Epub 2016 Jun 17. 4. Villa A, Woo SB. Leukoplakia — A diagnostic and management algorithm. J Oral Maxillofac Surg 2017 Apr;75(4):723–734. doi: 10.1016/j.joms.2016.10.012. Epub 2016 Oct 26. 5. Woo SB. Oral epithelial dysplasia and premalignancy. Head Neck Pathol 2019 Sep;13(3):423–439. doi: 10.1007/ s12105-019-01020-6. Epub 2019 Mar 18.

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Racial Disparity Among Adults With Oral Cancer Persists in the U.S. from 2000 to 2017 Abrar Bakhsh, DDS, and Caroline H. Shiboski, DDS, MPH, PhD

abstract Background: We investigated trends in incidence rates, stage at diagnosis and relative survival rates among adults with oral cancer in relation to race in the context of previously uncovered cancer-specific health disparities. Methods: We analyzed 2000--2017 SEER data among adults with oral cancer from 18 registries. We used SEER*Stat to compute proportions for each oral cancer site by stage at diagnosis and race and five-year relative survival rates by sex, cancer site, stage at diagnosis, age and race and explored trends over time. Results: Among 95,040 oral cancer cases reported to SEER, the most prevalent site was the tongue. While the rate among Black men decreased from 12.9 to 8/100,000, Blacks had significantly higher proportions of oral cancer that had spread at diagnosis than whites. Survival rates were substantially lower among Blacks than whites. Conclusions: The steep decline in oral cancer incidence rates in Black men is encouraging, although the persistent racial disparity with respect to late diagnosis and poor survival is alarming, requiring targeted interventions. Practical implications: Highlighting racial disparities with respect to oral cancer to increase awareness is the first step in developing interventions to address these disparities. Key words: Oral cancer, racial disparity, survival, stage at diagnosis, epidemiology

AUTHORS Abrar Bakhsh, DDS, is a resident in the postgraduate oral medicine and masters in oral and craniofacial sciences programs at the University of California, San Francisco, School of Dentistry. Conflict of Interest Disclosure: None reported.

Caroline H. Shiboski, DDS, MPH, PhD, is the Leland A. and Gladys K. Barber Distinguished Professor in Dentistry and chair of the department of orofacial sciences. She practices in the Sol Silverman Oral Medicine Clinic in the School of Dentistry at the University of California, San Francisco. Conflict of Interest Disclosure: None reported.

acial disparities with respect to cancer survival, with Black adults having significantly higher cancerrelated mortality than white adults, have been widely reported in the literature.1–10 The disparities uncovered by these studies pertain to cancers affecting a number of sites including breast and cervical cancer among women, prostate cancer among men and colorectal and lung cancer among both women and men.

While these disparities were identified from registry data from various regions in the U.S., the mortality associated with cervical cancer for example was found to be particularly high among non-Hispanic Black women in the South compared to 14 registries in non-Southern regions.10 Between 1992 and 2001, cancer of the oral cavity and pharynx was the fourth most common cancer and ranked 10th among the most common APRIL 2 0 2 1

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causes of death in Black men in the U.S.11 Oral cavity cancer can be diagnosed at an early stage by a routine visual inspection of the mouth. Stage at diagnosis of oral cancer is critically important, as it guides treatment and is the single most important predictor of outcome. A large tumor size, spread to regional lymph nodes, and presence of metastases in distant organs have been found to be closely related to poor survival.12–15 Therefore, it is critical to identify subgroups at higher risk for delayed diagnosis in an effort to develop screening strategies that will target these subgroups. We performed a previous analysis of data obtained from the National Cancer Institute (NCI)-supported 1973–2002 Surveillance Epidemiology and End Results (SEER) program16 to explore the distribution of stage at diagnosis and relative survival rates in a population of adults with oral cavity cancer (thought to be representative of the U.S. population) in relation to race over three decades.17 This analysis revealed that among nearly 50,000 cases of oral cavity cancer reported to the SEER program between 1973 and 2002, Black adults had significantly higher proportions of oral cavity cancer that had spread to a regional node or a more distant site at diagnosis than whites for all sites except for the lip. Black adults also experienced much lower five-year relative survival rates than whites. When we explored the five-year relative survival rate by stage at diagnosis for tongue cancer, it exceeded 55% in both Blacks and whites of either gender among cases that were localized at time of diagnosis, but there was still a difference between Blacks and whites among both men (56% versus 66%) and women (64% versus 71%). Among the cases of tongue 208 APRIL

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cancer that were found to have already spread at the time of diagnosis, survival was lower among Blacks than among whites (21% versus 37% among men and 28% versus 38% among women). Finally, we also found close to no improvement in either five-year relative survival or in how early oral cancer was diagnosed in either Blacks or whites between the earlier time period explored (1973–1987) and the later time period (1988–2002) explored in our previous study. Given the strong positive association between lower five-year

Oral cavity cancer can be diagnosed at an early stage by a routine visual inspection of the mouth.

relative survival and a later stage of cancer at diagnosis, we hypothesized that our previous finding of lower survival and later stage at diagnosis among adult Black men and women with oral cancer was likely explained by poor access to care. Thus, we wondered whether the proportion of late-stage diagnosis among adults with oral cancer, and the racial disparities previously uncovered for these cancers, may have recently decreased due to improved access to care associated with the implementation of the Affordable Care Act. Thus, the objective of the present study was to explore the distribution of stage at diagnosis and relative survival rates among adults with oral cavity cancer in relation to race within

the most recent available SEER database including cases reported to 18 registries in the U.S. from 2000 to 2017. We then compared these findings with our previous analyses using the 1973–2002 SEER database.

Methods Data Source and Variables

SEER is supported by the Surveillance Research Program (SRP) in the National Cancer Institute’s (NCI) Division of Cancer Control and Population Sciences (DCCPS).18 SRP is described as providing “national leadership in the science of cancer surveillance as well as analytical tools and methodological expertise in collecting, analyzing, interpreting and disseminating reliable population-based statistics.”18 SEER was established by the NCI in 1973 in response to the 1971 National Cancer Act and initially collected data from population-based cancer registries in nine geographic areas that together represented an estimated 10% of the U.S. population. The SEER program was subsequently expanded to a higher number of regions, which now collectively represent about 34% of the U.S. population.19 To expand on our previous analysis of the SEER 1973–2002 database, we selected the SEER 2000–2017 database from 18 registries representing about 28% of the U.S. population and the following geographic areas: Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San FranciscoOakland, Seattle-Puget Sound, Utah, Los Angeles, San Jose-Monterey, rural Georgia, Alaska Native Tumor Registry, greater California, Kentucky, Louisiana, New Jersey and greater Georgia. The SEER registry includes data on patient demographics, primary

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TABLE 1

Distribution of Oral Cavity Cancer Cases Reported to 18 Registries in the SEER Program 2000-2017 by Race, Age and Site All races

Whites

Blacks

Other

n (%)

n (%)a

20–44

6,107 (6)

4,954 (6)

567 (8)

586 (11)

45–54

16,010 (17)

13,281 (16)

1,813 (33)

916 (17)

55–64

26,788 (28)

23,021 (28)

2,394 (33)

1,373 (25)

≥ 65

46,135 (49)

41,179 (50)

2,432 (34)

2,533 (47)

Tongue

51,185 (54)

44,490 (54)

3,687 (51)

3,008 (56)

Gingiva and other mouth

23,734 (25)

19,557 (24)

2,345 (33)

1,832 (34)

Lip

11,064 (12)

10,727 (13)

149 (2)

188 (4)

Floor of mouth

9,057 (10)

7,652 (9)

1,025 (14)

380 (7)

Total

95,040b

82,426 (87)

7,206 (8)

5,408 (6)

(75)

(12)

(13)

We used the SEER*Stat software Version 8.3.820 and Stata version 16.121 for analyses presented in this article. Counts and proportions of cancers of the oral cavity were summarized by race in relation to age group and specific site. We computed proportions for each site by stage at diagnosis (localized versus spread to regional lymph nodes or to a distant site) among whites, Blacks and other races. We used a chi-square test to compare Blacks and other races to whites with respect to stage at diagnosis (localized versus spread) for each site. We used a life table method to compute survival rates. The five-year relative survival rate is defined as the likelihood that a person will not die of their cancer (or related cause) five years after the date of diagnosis.22,23 We computed five-year relative survival rates in both whites and Blacks, as the two predominant groups, by sex and by specific site. We also explored the five-year relative survival rates for persons with tongue cancer among whites and Blacks by gender, stage at diagnosis and age group (20–44 years versus ≥ 45 years). We estimated incidence rates, defined as the number of new cases

Age (years)

tumor site, morphology/histology and stage at diagnosis. Information on vital status is actively followed. We restricted our analyses to adults aged 20 or older with invasive cancer (no in situ cases) affecting the oral cavity. Salivary gland cancers were excluded because the histology of these tumors differs from that of the mouth where the vast majority of cancers are squamous cell carcinomas. Oral cavity sites are grouped into the SEER database as lip, tongue, floor of mouth (FOM) and “gum and other mouth.”

Statistical Analysis

Site

2000 U.S. Census (%)

Column percent may not total 100 due to rounding. The total number of cases of oral cavity cancers reported to the SEER program’s 18 registries was 96,005 and included 965 cases with unknown race status.

a b

per 100,000 persons, by race/ethnicity and gender. When relevant, rates were age adjusted to the 2000 U.S. standard million population. We computed the percent change (PC) and the estimated annual percent change (APC) from 2000 through 2017. The APC is computed by fitting a least square regression line to the natural logarithm of the rates using calendar year as a regressor variable.22,23 Testing the hypothesis that the APC = 0 is equivalent to testing the hypothesis that the regression parameter is equal to zero. The hypothesis is rejected at a significance level of P < 0.05.

(TA BLE 1 ). The distribution of cases by racial groups differed from the 2000 U.S. Census mainly in the proportion of whites being slightly higher among the oral cancer cases reported to the SEER program from 2000 to 2017 than the proportion of whites in the general population (87% versus 75%). The most prevalent site affected in all racial groups was the tongue (54% of oral cavity cases), while the lip was the least common site in Blacks and other non-white groups (2% and 4%, respectively).

Results Distribution of Oral Cancer Cases by Race, Age and Site

The age-adjusted incidence rate of oral cancer among white men increased slightly over time from 12.8/100,000 to 12.9/100,000, with an APC of + 0.4 (p < 0.05), which was statistically significantly greater than zero. However, the ageadjusted oral cancer rate among Black men decreased significantly during the same time period from 12.9 to 8/100,000 (PC = –38.4; APC = –2.8; p < 0.05).

A total of 95,040 cases of oral cancer were reported to 18 SEER registries between 2000 and 2017. The majority of oral cancer cases (77%) were diagnosed in persons ≥ 55 years of age, while 6% of cases were in young adults aged 20–44

Trends in Oral Cancer Rates Among U.S. Adults 2000–2017

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TABLE 2

Comparison by Race and Stage at Diagnosis for Site-Specific Oral Cancer Cases Reported to 18 Registries in the SEER Program 2000–2017 Localized

Regional/ distanta

n (%)b

Whites

15,235 (34)

27,358 (62)

Blacks

790 (21)

2,734 (74)

Other

1,448 (48)

1,409 (47)

Site

Unstaged p-valuec

Total

n (%)b

Tongue 1,897 (4)

44,490

< 0.0001

163 (4)

3,687

< 0.0001

151 (5)

3,008

5,338 (27)

19,557

Gingiva and other mouth Whites

6,291 (32)

7,928 (41)d

Blacks

583 (25)

1,077 (46)

< 0.0001

685 (29)

2345

Other

596 (33)

869 (47)d

0.009

367 (20)

1832

Whites

9,292 (87)

627 (6)

808 (8)

10,727

Blacks

118 (79)

22 (15)

< 0.0001

9 (6)

149

Other

158 (84)

17 (9)

0.07

13 (7)

188

Whites

3,369 (44)

3,941 (52)

342 (5)

7,652

Blacks

310 (30)

682 (67)

< 0.0001

33 (3)

1,025

Other

163 (43)

192 (51)

0.95

25 (7)

380

Lip

Floor of mouth

Spread to regional lymph nodes or to a more distant site. Row percent. c p-value for chi-square test comparing Blacks and other races to whites. d The percentage of cases with unknown stage in this category is high (> = 20%), which makes the row percent for regional/distant cases appear overall lower than in other sites. When computing the row percent based on known stage only, the percentages of regional/distant cases among whites, Blacks and other are 56%, 65% and 71%, respectively. a b

TABLE 3

Five-Year Relative Survival Rates for Persons With Oral Cancer by Sex, Race and Site: Data From 18 Registries in the SEER Program 2000–2017 Tongue

Gingiva/FOMa other mouth

Lip

5-yr RS (95% CI)b

White

25,152

66 (65; 67)

11,424

55 (54; 56)

6,181

90 (89; 92)

Black

2076

40 (37; 42)

1,643

43 (40; 45)

77 (60; 87)

White

9,501

64 (63; 65)

7,967

61 (59; 62)

2,180

90 (87; 92)

Black

827

41 (37; 45)

1,039

58 (54; 61)

83 (65; 92)

Men

Women

FOM: Floor of mouth. 5-yr RS: Five-year relative survival, expressed as percent, defined as the likelihood that a person will not die from cancer-related causes five years after diagnosis; 95% CI: 95% confidence interval for the five-year RS. All percentages are rounded to the nearest whole number.

a b

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The age-adjusted incidence rate among white women was unchanged over time and around 6/100,000, while the age-adjusted rate of oral cancer among Black women significantly decreased from 3.8 to 2.7/100,000 during the same period with an APC of –2.1 (p < 0.05).

Stage at Diagnosis for Oral Cancer Among White and Black Adults by Site and Over Time

Among Black adults with tongue cancer, 74% of cases were diagnosed after having spread to a regional or distant site compared to 62% of cases among white adults (TA BLE 2 ). When comparing the two groups using a chi-square test, the difference was found to be statistically significant. Among other race groups, the proportion of cases with tongue cancer that had spread was significantly lower (47%). A similar contrast between Black and white adults was observed with respect to FOM cancer with 67% having spread at time of diagnosis among Blacks compared to 52% among whites (p < 0.0001). The proportion of FOM cancer that had spread at time of diagnosis among other race groups (51%) was similar to that among whites. The lip was the only site where the vast majority of cases were diagnosed at an early stage (when still localized) in all race groups. However, there was still a significantly higher proportion of Blacks with lip cancer that had spread to a regional or distant site at time of diagnosis compared to whites (15% versus 6%).

Site-Specific Relative Survival for White and Black Adults With Oral Cancer

Among adults with oral cancer reported to 18 registries of the SEER program from 2000 to 2017, the lowest five-year relative survival rates were observed among Black men and women

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TABLE 4

Five-Year Relative Survival Rates for Persons With Tongue Cancer by Sex and Race and by Stage at Diagnosis:a Data From 18 Registries in the SEER Program 2000–2017 Localized

with tongue cancer (40% and 41%, respectively, TA BLE 3 ). The five-year relative survival rates observed in white men and women with tongue cancer were higher (66% and 64%, respectively). The contrast in survival rates between Blacks and whites was not as pronounced for cancer of the FOM, gingiva and other oral cavity sites, in particular among women (58% versus 61%). The highest fiveyear relative survival rate was seen among adults with lip cancer, ranging from 77% among Black men to 90% among white men and women.

Discussion

A total of 95,040 cases of oral cancer were reported to 18 SEER registries that represent about 28% of the U.S. population between 2000

5-yr RS (95% CI)

5-yr RS (95% CI)c

White men

6,258

80 (79; 81)

18,041

62 (61; 63)

Black men

285

58 (50; 65)

1,726

37 (34; 39)

White women

4,498

79 (78; 81)

4,581

50 (49; 52)

Black women

231

68 (60; 75)

561

30 (26; 34)

Does not include cases with unknown stage at diagnosis. Spread to regional lymph nodes or to a more distant site. c 5-yr RS: Five-year relative survival, expressed as percent, defined as the likelihood that a person will not die from cancer-related causes five years after diagnosis; 95% CI: 95% confidence interval for the five-year RS. All percentages are rounded to the nearest whole number. a b

TABLE 5

Five-Year Relative Survival Rates for Persons With Tongue Cancer by Sex and Race and by Age at Diagnosis:a Data From 18 Registries in the SEER Program 2000–2017 20–44 years

Relative Survival in Adults With Tongue Cancer by Stage at Diagnosis and Age

We explored the five-year relative survival rate among adults with tongue cancer in relation to stage at diagnosis and found that it ranged from 58% among Black men to 80% among white men who had the highest rate when the cancer was localized at time of diagnosis (TA BLE 4 ). Among cases of tongue cancer that had spread to a regional or distant site at time of diagnosis, the five-year relative survival rate was lowest among Black women and men (30% and 37%, respectively) and highest among white men (62%). Among young adults aged 20–44 years, the five-year relative survival rates among white men and women with tongue cancer (72% and 75%, respectively) appeared substantially higher than the rates among Black men and women (44% and 52%, respectively, TA BLE 5 ).

Regional/distant b c

White men

≥ 45 years

5-yr RS (95% CI)

1,654

72 (70; 75)

5-yr RS (95% CI)b

21,504

65 (64; 66)

Black men

139

44 (35; 53)

1,717

39 (36; 42)

White women

994

75 (72; 78)

7,820

63 (61; 64)

Black women

52 (41; 62)

639

39 (35; 44)

Does not include cases with unknown stage at diagnosis. 5-yr RS: Five-year relative survival, expressed as percent, defined as the likelihood that a person will not die from cancer-related causes five years after diagnosis; 95% CI: 95% confidence interval for the five-year RS. All percentages are rounded to the nearest whole number.

a b

and 2017. The most prevalent site affected in all racial groups was the tongue (54% of oral cavity cases), while the lip was the least common site in Blacks and other nonwhite groups (2% and 4%, respectively). This was consistent with our previous analysis of 50,000 cases of oral cavity cancer reported to the SEER program between 1973 and 2002.17 However, differences were observed between the two time periods with respect to trends in age-adjusted oral cancer rates over time. From 2000 to 2017, a very slight increase was observed among white men, to 12.9/100,000 in 2017, which contrasted with the sharp decrease observed from 1973

to 2002. Meanwhile, the rate among Black men decreased significantly from 12.9 to 8/100,000, a continuation of the trend observed from 1973 to 2002. Furthermore, the oral cancer rates continued to decrease among Black women, from 3.8 to 2.7/100,000 from 2000 to 2017, compared to 5.1/100,000 in 1973. White women experienced no change in age-adjusted oral cancer rates from 2000 to 2017 with rates being strikingly similar to those observed from 1973 to 2002 around 6/100,000. Disappointingly, Black adults continued to have significantly higher proportions of oral cavity cancer that had spread to a regional node or a more distant site APRIL 2 0 2 1

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at diagnosis than whites for all sites, including the lip. The proportion of tongue cancer that had spread to a regional/distant site was actually higher among both Blacks and whites (74% and 62%, respectively) from 2000 to 2017 than from 1988 to 2002 (70% and 53% respectively). While the recent proportions could be affected by a slightly different approach to staging in the more recent time period, they remain alarmingly high for cancer of a site that is accessible to visual examination and should thus be diagnosed at an earlier stage. The five-year relative survival rate was substantially lower among Black men and women (40% and 41%, respectively) than among white men and women (66% and 64%, respectively). However, these rates were about 10% higher among both Black and white men than in the 1988–2002 time interval where we found it to be 31% and 53%, respectively.17 Less change in survival was observed among women of either race. Similarly to our earlier analysis, the highest five-year relative survival rates in both Blacks and whites were observed among those with cancer of the lip. When we explored the five-year relative survival rates by stage at diagnosis, we found a marked improvement among white men for both localized and regional/distant metastatic tongue cancer (80% and 62%, respectively, versus 66% and 37% in 1973–2002). However, there was no improvement in survival rates among Black men and women with localized tongue cancer in 2000–2017 (58% and 68%, respectively) nor among Black women with regional/ distant metastatic tongue cancer (30%). The five-year relative survival rate among Black men with tongue 212 APRIL

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cancer that had spread to a regional/ distant site improved from a dismal 21% in 1973–2002 to 37% in 2000– 2017, although the difference with the survival rate among white men (62%) was substantially larger than in the earlier time period. Younger (20–44 years) Black men and women with tongue cancer were found to have substantially higher five-year relative survival rates in 2000–2017 (44% and 52%, respectively) than in 1973–2002 (29% and 24%, respectively), although they remained much lower than among

The highest five-year relative survival rates in both Blacks and whites were observed among those with cancer of the lip.

white men and women in the current study (72% and 75%, respectively). Racial disparities with respect to diagnosis at more advance stages of disease and lower survival rates among Blacks compared to whites continue to be reported for a number of cancer sites including lung, breast, testicular, colorectal and oral cancers and gastrointestinal stromal tumors.17,24–29 The cause of these racial disparities is undoubtedly multifactorial, and poor access to care among the uninsured or Medicaid recipients, the presence of comorbidities and differences in tumor molecular subtypes for certain types of cancers have been suggested as potential explanations. In the U.S., access to care differs substantially across geographical locations, as

illustrated by one study that observed age-adjusted rates of colorectal cancer among Black men that were more than twice as high in rural Georgia (31/100,000) than in California (13/100,000).28 Interestingly, a matched-pair study that controlled for several potentially confounding prognostic variables among patients who received similar multidisciplinaryteam directed treatment at a tertiary cancer center uncovered no evidence of disparities in survival among Black or Hispanic adults with head and neck cancer compared to non-Hispanic whites.30 Similarly, one study among U.S. veterans with early-stage lung cancer from 2001 to 2010 found no racial difference in overall survival and lung cancer-specific survival, likely due to the equal access within the VA Health Care system.31 A recent analysis of data on cervical cancer reported to the SEER program from 2007 to 2011, after health insurance status became a variable collected by SEER registries, revealed a higher mortality among the uninsured and those on Medicaid.32 A study analyzing recent SEER oral cavity squamous cell carcinoma data among 7,630 cases reported from 2010 to 2014 found that the greater mortality for Blacks versus whites was largely attributed to the higher prevalence of later stage at presentation and being uninsured among Blacks.33 However, another study of disparities in mortality from laryngeal cancer found that while Blacks had significantly higher cancer-specific mortality than whites in univariate analyses, this association no longer remained in multivariate analysis when controlling among other variables for sociodemographic variables.34 These findings are not limited to cancer, as shown by an extensive analysis of

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data on socioeconomic disparities in health in the U.S. obtained from five nationally representative data sources by Braveman and colleagues.35 This study reported that those with the lowest income and who were least educated were consistently least healthy with lower life expectancy, activity limitation due to chronic disease, diabetes and obesity. Similarly, an analysis of the 2016 National Health and Nutrition Interview Survey revealed that minority racial/ethnic groups were less likely to have received an oral cancer screening in the past two years than whites.36 In particular, 19% of non-Hispanic Blacks compared to 47% of non-Hispanic whites reported receiving an intraoral examination in the past two years. Medical mistrust, with Black patients reporting greater mistrust than white patients, has been identified as contributing to racial health disparities in a number of studies.37–41 These studies have revealed mistrust of health care organizations in general, in primary care, HIV care and cardiac care. Studies have also started to explore unconscious bias and subtle discrimination that produce less favorable outcomes for Blacks than for whites, contribute to error and miscommunication and create racial distrust.42 The study of cultural differences, attitudes and behaviors that may lead to both medical distrust and unconscious bias is a positive development in health disparities research because such knowledge will hopefully contribute to the implementation of new interventions to alleviate such distrust and bias. The strengths inherent to the SEER program include its very large population-based datasets of all cancer cases reported in diverse geographic regions that together represent up to 34% of the U.S. population and

the 45-year duration of this ongoing program allowing for the study of trends in cancer incidence across time. The main limitation of the SEER database is that it does not permit the exploration of a number of potential contributing factors to the uncovered racial disparities. However, since 2007, health insurance status is being reported, which will provide valuable information pertaining to health disparities in analyses moving forward. While the continuation of the steep decline in age-adjusted incidence rate of oral cancer in Black men and the low incidence rate of oral cancer among Black women from 2000 to 2017 is cause for optimism, the persistent racial disparity with respect to late diagnosis and poor survival is a cause for great concern. It may be too early to observe any impact of the Affordable Care Act on higher utilization of care. Furthermore, the disparities may be partly explained by medical distrust, which is often associated with unconscious or implicit bias. Thus, future strategies to correct these disparities, in addition to improved access to care, will imperatively need to include interventions to improve cultural competency among medical and dental providers and to reduce medical distrust among Blacks and other underserved populations. With respect to strategies aimed at improving early detection of oral cancer in all populations, and as mentioned in our previous paper on this topic,17 primary care physicians and nurse practitioners could play an important role in the initial screening for oral cancer if they were trained in performing an oral soft tissue examination. Such visual inspection of the mouth is easy to perform, and the nondental

professional can easily be trained to identify a nonhealing ulcer or a persistent white and/or red plaque that may represent a precancerous lesion that should be further evaluated and biopsied by either an oral medicine specialist or an oral surgeon. n RE FEREN CE S 1. Du W, Simon MS. Racial disparities in treatment and survival of women with stage I–III breast cancer at a large academic medical center in metropolitan Detroit. Breast Cancer Res Treat 2005 Jun;91(3):243–8. doi: 10.1007/s10549-005-0324-9. 2. Elmore JG, Nakano CY, Linden HM, et al. Racial inequities in the timing of breast cancer detection, diagnosis, and initiation of treatment. Med Care 2005 Feb;43(2):141–8. doi: 10.1097/00005650-200502000-00007. 3. Ward E, Jemal A, Cokkinides V, et al. Cancer disparities by race/ethnicity and socioeconomic status. CA Cancer J Clin Mar–Apr 2004;54(2):78–93. doi: 10.3322/ canjclin.54.2.78. 4. Underwood W, DeMonner S, Ubel P, et al. Racial/ ethnic disparities in the treatment of localized/regional prostate cancer. J Urology 2004 Apr;171(4):1504–7. doi: 10.1097/01.ju.0000118907.64125.e0. 5. Chang K, Parasher G, Christie C, Largent J, Anton-Culver H. Risk of pancreatic adenocarcinoma. Disparity between African Americans and other race/ethnic groups. Cancer 2005 Jan 15;103(2):349–57. doi: 10.1002/cncr.20771. 6. Tammemagi C, Nerenz D, Neslund-Dudas C, Feldkamp C, Nathanson D. Comorbidity and survival disparities among black and white patients with breast cancer. JAMA 2005 Oct 12;294(14):1765–72. doi: 10.1001/jama.294.14.1765. 7. DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 2017 Nov;67(6):439–448. doi: 10.3322/caac.21412. Epub 2017 Oct 3. 8. Ellis L, Canchola AJ, Spiegel D, et al. Racial and ethnic disparities in cancer survival: The contribution of tumor, sociodemographic, institutional and neighborhood characteristics. J Clin Oncol 2018 Jan 1;36(1):25–33. doi: 10.1200/JCO.2017.74.2049. Epub 2017 Oct 16. 9. Singh GK, Jemal A. Socioeconomic and racial/ethnic disparities in cancer mortality, incidence and survival in the United States, 1950–2014: Over six decades of changing patterns and widening inequalities. J Environ Public Health 2017;2017:2819372. doi: 10.1155/2017/2819372. 10. Yoo W, Kim S, Huh WK, et al. Recent trends in racial and regional disparities in cervical cancer incidence and mortality in United States. PLoS One 2017 Feb 24;12(2):e0172548. doi: 10.1371/journal.pone.0172548. eCollection 2017. 11. Jemal A, Clegg L, Ward E, et al. Annual report to the nation on the status of cancer, 1975–2001, with a special feature regarding survival. Cancer 2004 Jul 1;101(1):3–27. doi: 10.1002/cncr.20288. 12. Baatenburg de Jong RJ, Hermans J, Molenaar J, Briaire JJ, le Cessie S. Prediction of survival in patients with head and neck cancer. Head Neck 2001 Sep;23(9):718–24. doi: 10.1002/hed.1102. 13. Chandu A, Adams G, Smith AC. Factors affecting survival APRIL 2 0 2 1

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in patients with oral cancer: An Australian perspective. Int J Oral Maxillofac Surg 2005 Jul;34(5):514–20. doi: 10.1016/j.ijom.2004.10.006. 14. Kurokawa H, Zhang M, Matsumoto S, et al. The high 23A prognostic value of the histologic grade at the deep invasive front of tongue squamous cell carcinoma. J Oral Pathol Med 2005 Jul;34(6):329–33. doi: 10.1111/j.16000714.2005.00244.x. 15. Noguchi M, Kido Y, Kubota H, Kinjo H, Kohama G. Prognostic factors and relative risk for survival in N1-3 oral squamous cell carcinoma: a multivariate analysis using Cox’s hazard model. Br J Oral Maxillofac Surg 1999 Dec;37(6):433–7. doi: 10.1054/bjom.1999.0146. 16. National Cancer Institute. Surveillance, Epidemiology et al. (seer.cancer.gov/) SEER*Stat Database — SEER 9 Regs Public-Use, Nov 2004 Sub (1973–2002). National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, April 2005 release, based on the November 2004 submission. 17. Shiboski CH, Schmidt BL, Jordan RC. Racial disparity in stage at diagnosis and survival among adults with oral cancer in the US. Community Dent Oral Epidemiol 2007 Jun;35(3):233–40. doi: 10.1111/j.03015661.2007.00334.x. 18. National Cancer Institute Surveillance, Epidemiology and End Results Program. seer.cancer.gov. Accessed Jan. 28, 2021. 19. Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2017, National Cancer Institute. Bethesda, Md., based on November 2019 SEER data submission, posted to the SEER website, April 2020. seer. cancer.gov/csr/1975_2017. 20. National Cancer Institute Surveillance Epidemiology and End Results (SEER) Program. SEER*Stat Database: Incidence SEER Research Data, 18 Registries, Nov 2019 Sub (2000–2017), National Cancer Institute, DCCPS, Surveillance Research Program released April 2020 based on the November 2019 submission. seer.cancer.gov. 21. StataCorp. Stata Statistical Software. Release 16.1 ed. College Station, Texas: Stata Corporation; 2021. 22. Kleinman DV, Crossett LA, Ries LAG, et al. Cancers of the Oral Cavity and Pharynx: A statistics review monograph, 1973–1987. Atlanta: USDHHS, Public Health Services, Centers for Disease Control and National Institute of Health; 1991. 23. Ries L, Eisner M, Kosary C, et al. SEER Cancer Statistics Review, 1975–2002. National Cancer Institute. Bethesda, Md. 2005. seer.cancer.gov/csr/1975_2002. 24. Hardy D, Du DY. Socioeconomic and racial disparities in cancer stage at diagnosis, tumor size and clinical outcomes in a large cohort of women with breast cancer, 2007–2016. J Racial Ethn Health Disparities 2020 Sep 10. doi: 10.1007/ s40615-020-00855-y. Online ahead of print. 25. Kong X, Liu Z, Cheng R, et al. Variation in breast cancer subtype incidence and distribution by race/ethnicity in the United States from 2010 to 2015. JAMA Netw Open 2020 Oct 1;3(10):e2020303. doi: 10.1001/ jamanetworkopen.2020.20303. 26. Yedjou CG, Sims JN, Miele L, et al. Health and racial disparity in breast cancer. Adv Exp Med Biol 2019;1152:31– 49. doi: 10.1007/978-3-030-20301-6_3. 27. Ulanja MB, Rishi M, Beutler BD, et al. Racial disparity in incidence and survival for gastrointestinal stromal tumors (GISTs): An analysis of SEER database. J Racial Ethn Health

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Disparities 2019 Oct;6(5):1035–1043. doi: 10.1007/ s40615-019-00605-9. Epub 2019 Jun 18. 28. Abualkhair WH, Zhou M, Ochoa CO, et al. Geographic and intra-racial disparities in early-onset colorectal cancer in the SEER 18 registries of the United States. Cancer Med 2020;9(23):9150–59. doi.org/10.1002/cam4.3488. 29. Morse DE, Kerr AR. Disparities in oral and pharyngeal cancer incidence, mortality and survival among Black and white Americans. J Am Dent Assoc 2006 Feb;137(2):203– 12. doi: 10.14219/jada.archive.2006.0146. 30. Chen LM, Li G, Reitzel LR, et al. Matched-pair analysis of race or ethnicity in outcomes of head and neck cancer patients receiving similar multidisciplinary care. Cancer Prev Res (Phila) 2009 Sep;2(9):782–91. doi: 10.1158/1940-6207.CAPR09-0154. Epub 2009 Sep 8. 31. Williams CD, Salama JK, Moghanaki D, Karas TZ, Kelley MJ. Impact of race on treatment and survival among U.S. veterans with early-stage lung cancer. J Thorac Oncol 2016 Oct;11(10):1672–81. doi: 10.1016/j.jtho.2016.05.030. Epub 2016 Jun 11. 32. Churilla T, Egleston B, Dong Y, et al. Disparities in the management and outcome of cervical cancer in the United States according to health insurance status. Gynecol Oncol 2016 Jun;141(3):516–523. doi: 10.1016/j. ygyno.2016.03.025. Epub 2016 Mar 25. 33. Yu AJ, Choi JS, Swanson MS, et al. Association of race/ethnicity, stage, and survival in oral cavity squamous cell carcinoma: A SEER study. OTO Open 2019 Dec 10;3(4):2473974X19891126. doi: 10.1177/2473974X19891126. eCollection Oct–Dec 2019. 34. Chen S, Dee EC, Muralidhar V, et al. Disparities in mortality from larynx cancer: Implications for reducing racial differences. Laryngoscope 2020 Sep 1. doi: 10.1002/ lary.29046. Online ahead of print. 35. Braveman PA, Cubbin C, Egerter S, Williams DR, Pamuk E. Socioeconomic disparities in health in the United States: What the patterns tell us. Am J Public Health 2010 Apr 1;100 Suppl 1(Suppl 1):S186–96. doi: 10.2105/AJPH.2009.166082. Epub 2010 Feb 10. 36. Gupta A, Sonis S, Uppaluri R, Bergmark RW, Villa A. Disparities in oral cancer screening among dental professionals: NHANES 2011–2016. Am J Prev Med 2019 Oct;57(4):447–457. doi: 10.1016/j.amepre.2019.04.026. Epub 2019 Aug 20. 37. Arnett MJ, Thorpe RJ Jr., Gaskin DJ, Bowie JV, LaVeist TA. Race, medical mistrust and segregation in primary care as usual source of care: Findings from the exploring health disparities in integrated communities study. J Urban Health 2016 Jun;93(3):456–67. doi: 10.1007/s11524-016-00549. 38. Doescher MP, Saver BG, Franks P, Fiscella K. Racial and ethnic disparities in perceptions of physician style and trust. Arch Fam Med Nov–Dec 2000;9(10):1156–63. doi: 10.1001/archfami.9.10.1156. 39. LaVeist TA, Isaac LA, Williams KP. Mistrust of health care organizations is associated with underutilization of health services. Health Serv Res 2009 Dec;44(6):2093–105. doi: 10.1111/j.1475-6773.2009.01017.x. Epub 2009 Sep 2. 40. Saha S, Jacobs EA, Moore RD, Beach MC. Trust in physicians and racial disparities in HIV care. AIDS Patient Care STDS 2010 Jul;24(7):415–20. doi: 10.1089/ apc.2009.0288.

41. LaVeist TA, Nickerson KJ, Bowie JV. Attitudes about racism, medical mistrust and satisfaction with care among African American and white cardiac patients. Med Care Res Rev 2000;57 Suppl 1:146–61. doi: 23B 10.1177/1077558700057001S07. 42. Dovidio JF, Penner LA, Albrecht TL, et al. Disparities and distrust: The implications of psychological processes for understanding racial disparities in health and health care. Soc Sci Med 2008 Aug;67(3):478–86. doi: 10.1016/j. socscimed.2008.03.019. Epub 2008 May 26. T HE CORRE S P ON DIN G AU T HOR , Caroline H. Shiboski, DDS, MPH, PhD, can be reached at caroline.shiboski@ucsf.edu.

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The Role of Dental Professionals in the Early Detection of Oral Cancer Kyle Jones, DDS, PhD

abstract Oral health care providers are uniquely positioned to expertly perform extra- and intraoral cancer screening exams, which can save patient lives. This article discusses the importance of performing oral cancer screenings as part of every comprehensive and periodic oral exam as well as factors that may prevent routine screening and biopsy of suspicious lesions. It also discusses how to approach patients with oral leukoplakia, erythroplakia and chronic, nonhealing ulcers. Key words: Oral cancer, oral cancer screening, oral leukoplakia, oral erythroplakia, chronic oral ulcers

AUTHOR Kyle Jones, DDS, PhD, is an assistant professor at the University of California, San Francisco, School of Dentistry. He is the director of the UCSF oral dysplasia program where he sees patients with oral dysplasia and other oral potentially malignant disorders. His research focuses on how the immune system is altered in head and neck precancerous lesions and tumors, with the goal of improving current immunotherapies for these diseases. Dr. Jones is also a diplomate of the American Board of Oral and Maxillofacial Pathology and provides histologic diagnostic services for oral and maxillofacial pathology specimens in the UCSF dermatopathology and oral pathology service. Conflict of Interest Disclosure: None reported.

ral and oropharyngeal cancers were estimated to affect over 53,000 people within the United States in 2020, resulting in over 10,000 deaths.1,2 Squamous cell carcinoma is the most common type of head and neck cancer, representing greater than 80% of all intraoral malignancies.3,4 Many oral cancers (i.e., those arising anterior to the tonsillar pillars and not in the oropharynx) arise from oral potentially malignant disorders (e.g., leukoplakia, erythroplakia, etc.) that can be identified during an intraoral exam by health care providers. Dentists, dental specialists, dental hygienists, dental assistants and all other oral health care providers are uniquely positioned to be able to identify benign, premalignant and malignant intraoral lesions given their specialized knowledge and experience working in the oral cavity. Identifying oral potentially malignant disorders or cancers early can save lives

and potentially minimize the need for significantly invasive cancer therapies.

Importance of Oral Cancer Screenings

Recent data from the Surveillance, Epidemiology and End Results (SEER) program show that oral cavity and pharynx cancer patients diagnosed with localized, premetastatic disease have five-year survival rates of up to 85%. However, once cancer cells have metastasized either locally (e.g., to the cervical lymph nodes in the neck) or distantly (e.g., outside of the head and neck region), the five-year survival rates fall precipitously to about 67% and 40%, respectively. These trends were nearly identical in patients with cancers arising on the tongue, the most common intraoral site for oral cancer (82%, 68% and 40%, respectively; see the corresponding articles in this issue for excellent reviews on risk factors and outcomes associated specifically with cancers arising in the oral cavity and APRIL 2 0 2 1

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SEER Oral Cavity and Pharynx Cancer 5-Year Relative Survival Rates, 2010–2016 100

Percent surviving

Black White

Localized disease 77.3 85.3

Regional metastases 51.7 68.1

Distant metastases 29.3 41.1

FIGURE 1. SEER data showing the disparities in five-year survival rates for Black and white patients with oral

cavity and oropharyngeal cancers, stratified by localized disease, regional metastases and distant metastases.2

oropharynx).2 Unfortunately, when stratified by race, Black people are disproportionately affected and have even worse survival outcomes in all three categories (FIGURE 1 ). Recent work from McDermott and colleagues explored this issue further, finding that Black patients presented at higher cancer stages with more advanced disease and received less treatment than other racial/ethnic groups.5 They also found that living in high-poverty areas and receiving health care at non-National Cancer Institute/ nonteaching hospitals were significantly associated with higher cancer stages and the type/amount of treatment rendered. Furthermore, they addressed the potential role of structural racism in the medical field stating that, “There are many data showing mistrust of the medical community among Black patients, in addition to the role of implicit bias and structural racism in the community, all of which can be associated with delayed or forgone medical care or refusal of ideal medical care. It is imperative for health care workers to educate themselves on racism and cultural differences and to 216 APRIL

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form trusting relationships with their patients to provide optimal cancer care.”5 Up to 70% of all new oral and oropharyngeal cases will be diagnosed at a late stage, underscoring the importance of early detection and treatment.6 Although data from clinical trials in the breast, uterine cervix and colon have shown that cancer screening exams can prevent the development of cancer at these sites and decrease site-specific cancer-related mortality, there remains a paucity of similar studies and evidence supporting the efficacy of routine oral cancer screenings for reducing oral cancer rates and related mortality.7–9 This has resulted in a lack of formal recommendations advocating for routine oral cancer screening exams from government regulatory bodies and advisory committees, including in the U.S.10,11 Thus far, only one randomized cluster-controlled trial has been conducted evaluating the utility of oral visual cancer screening on overall oral cancer mortality rates.12,13 The study was based in Kerala, India, and used a clustering approach of 13 distinct municipalities within Kerala in which subjects in seven interventional clusters

(n = 96,517) received an oral visual cancer screening while subjects in six control clusters (n = 95,356) received standard of care on three separate occasions between 1996 and 2004. Screenings were performed by trained, nonmedical university graduates. Although there was no statistically significant difference 1B between overall oral cancer mortality rates in control and intervention groups (RR 0.88; 95% CI 0.69 to 1.12), a subgroup analysis revealed a 24% reduction in mortality in high-risk subjects who used tobacco and/or alcohol (RR of 0.76%; 95% CI 0.60 to 0.97).13 As others have rightfully pointed out, the study suffered from issues related to study design, adequate subject follow up and proper statistical analysis, making its generalizability to other populations challenging. However, the study does provide some support for the utility of oral cancer screening in potentially high-risk patients. Further analysis showed that overall 269 life years were saved per 100,000 patient years for all individuals and 1,438 lives saved among the high-risk subgroups.10 Additional randomized controlled trials are certainly needed to substantiate these findings, especially in geographic areas (e.g., Western countries) where the incidence rates of oral cancer are far lower. Despite the lack of strong evidence supporting the widespread use of oral visual and tactile cancer screening exams on all adult patients in the dental setting, performing these exams seems reasonable given that providers incur relatively few costs to perform them (e.g., a few additional minutes of chair time) and the screenings are relatively easy to integrate with standard comprehensive or periodic oral exams (COE and POE). Furthermore, the fact that patients diagnosed with earlier-stage oral cancers have significantly improved five-year survival rates compared to those with regional and/or distant

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metastatic disease further supports this practice.2 Based on a recent meta-analysis from an American Dental Association (ADA) convened expert panel, the ADA advocates that, “Clinicians should obtain an updated medical, social and dental history and perform an intraoral and extraoral conventional visual and tactile examination in all adult patients.4,14 Likewise, the American Academy of Oral Medicine also supports performing a “… noninvasive visual and tactile oral mucosal examination as part of the standard initial and recall examination for all patients.”15 A Cochrane review by Walsh and colleagues as well as recent analysis by Brocklehurst and Speight found that although the sensitivity for detecting oral potentially malignant disorders in healthy adults by COE was somewhat variable, it was almost always greater than 70% while specificity was consistently greater than 90%.10,16 Despite these recommendations along with the evidence illustrating the importance of early oral cancer detection, recent work by Gupta and colleagues revealed that only a minority of U.S. dental patients who visited a dentist in the last two years reported having either extraoral (31.3%) or intraoral (37.6%) cancer screening exams performed.17 They also found that minority racial/ethnic groups, less-educated, uninsured/Medicaid-insured and lowincome patients, independent of smoking and alcohol use, were significantly less likely to have reported receiving extraand intraoral cancer screening exams, indicating the presence of additional conscious and/or unconscious provider biases that may affect which patients are screened.17 As the authors rightfully point out in this study, these self-reported metrics likely underestimate the true number of patients who received an oral cancer screening by a dental professional due to patient recall bias. However, the findings highlight several important points:

Extra- and intraoral cancer screening rates are likely less than ideal in U.S. dental practices. ■ There appears to be a lack of clear communication between providers and patients such that patients understand that an oral cancer screening exam has taken place. ■ It is likely that both unconscious and conscious provider biases affect which patients receive extra- and intraoral cancer screenings. While there are likely multiple factors at play precluding dental professionals ■

Cigarette smoking and alcohol use, especially when used in combination, are the largest risk factors for developing oral cancer.

from routinely performing oral cancer screenings in their practices (some of which will be addressed below), there is a relatively simple solution to this seemingly complex problem: Dental professionals should perform extra- and intraoral cancer screening exams for every adult patient, regardless of associated risk factors, education level, race/ethnicity, insurance status, etc. Not only is it relatively easy and feasible to integrate these screenings with COEs and POEs, but it can also be a great practice builder that increases trust and communication between patients and providers.

The Nuts and Bolts of Extra- and Intraoral Screening Exams

With some practice, performing extraand intraoral exams for dental patients

is typically a fast, straightforward and painless process that can be carried out in the dental chair as part of any COE or POE. While there are many ways to perform extra- and intraoral cancer screenings, it is recommended that dental professionals follow the same process for each patient in order to not inadvertently miss reviewing a particular anatomic structure or area (TA BLE ). Excellent reviews and videos about how to perform extra- and intraoral examinations can be found online.18,19 Additionally, it is important to clearly explain to patients that extra- and intraoral cancer-screening exams will be performed as part of their COE or POE. This allows patients to ask any questions they might have, especially those related to oral cancer risk reduction strategies (e.g., reducing smoking and alcohol use) and further reinforces the provider’s role as an oral health care provider. It is also a great opportunity to educate patients about common risk factors associated with oral and oropharyngeal cancers (e.g., tobacco, alcohol and betel quid use for oral cancers and high-risk human papilloma virus infection in oropharyngeal cancers). A cross-sectional study of dental patients in the United Kingdom revealed that 77% of respondents knew “a little” or “nothing at all” about oral cancer, 72% did not know that dentists perform extra- and intraoral cancer screenings, 92% wanted to be alerted if their dentist was going to perform such an exam and 97% would welcome help from their dentist in reducing the risk of getting oral cancer.20 Cigarette smoking and alcohol use, especially when used in combination, are the largest risk factors for developing oral cancer, with increasing risk based on the frequency and duration of use.21 Other modifiable risk factors, such as chewing tobacco, betel quid chewing and UV light exposure (for lip cancers), have all been associated with oral cancer.22 APRIL 2 0 2 1

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TABLE

Components of Extra- and Intraoral Cancer Screening Exams Extraoral (i.e., head and neck) cancer screening exam System/Area

Components Reviewed

Constitutional

Is the patient well-developed, well-nourished or in any distress?

Psychiatric/neurologic

Patient oriented to person, place and time. Deficits in motor function of the head and neck including muscles of facial expression.

Skin

Rashes, ulcers, pigmented lesions or any other suspicious lesions.

Voice

Quality of voice (e.g., strong versus hoarse, breathy or raspy).

Head/face/lips

Signs of asymmetry, swelling, masses or other suspicious lesions on the face, lips and major salivary glands on visual inspection and palpation.

Neck

Signs of asymmetry, swelling, tenderness, masses or lymphadenopathy in the neck or thyroid gland on visual inspection and palpation.

Intraoral cancer screening exam System/Area

Components Reviewed

Upper and lower labial mucosa

For all intraoral soft tissues, look for signs of mucosal swellings, ulcers, color changes (e.g., leukoplakia/erythroplakia), surface texture changes and palpable masses.

Bilateral buccal mucosa

See above

Facial and lingual gingiva on the maxilla and mandible

See above

Tongue (dorsal and lateroventral surfaces)

See above

Floor of mouth

See above

Hard palate

See above

Soft palate/oropharynx

See above

Tonsils (if present) and faucial pillars

Signs of asymmetry, swelling, inflammation and/or masses in tonsils.

Dentition

Shifted and/or loose teeth; overall state of dentition.

Additionally, infection by high-risk HPV subtypes, especially types 16 and 18, are associated with 70% of oropharyngeal cancers.23 These are all areas in which oral health care professionals can counsel patients in order to take a more holistic approach to the patient’s overall oral health. For those patients interested in smoking/tobacco cessation, various local, state and national programs exist to assist them in this endeavor. Smokefree.gov is a great resource for both patients and providers and contains lots of helpful resources for quitting, phone apps that can help facilitate the process and contact information for trained smokingcessation coaches. The Substance Abuse and Mental Health Services Administration (SAMHSA) through the U.S. Department of Health and Human 218 APRIL

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Services is another excellent resource for individuals and families facing mental and/or substance use disorders such as alcohol and tobacco addiction. A helpline is available 24-hours-a-day, 365-days-a-year at 800-662-HELP.

Oral Cancer Screening Adjuncts

Several screening adjuncts have been marketed to oral health care providers to aid in identifying premalignant and malignant changes within the oral cavity; however, there is limited evidence to support their utility as general screening tools over a traditional visual and tactile exam alone. Additionally, some authors have expressed concerns of bias in the few studies that have been published supporting their use.4 Examples of additional screening adjuncts include

cytologic testing (i.e., brush biopsy), autofluorescence (e.g., VELscope), tissue reflectance (e.g., ViziLite Plus), vital staining (e.g., toluidine blue) and saliva DNA analyses. Lingen and colleagues, as part of an ADA convened expert panel in 2017, compiled an outstanding review and analysis of these types of oral cancer screening adjuncts and made expert recommendations for their use. For lesions concerning for premalignant or malignant changes, the panel recommended performing a biopsy with histopathologic examination or referral to a specialist as soon as possible. In general, screening adjuncts were not recommended “… for the evaluation of potentially malignant disorders among adult patients with clinically evident, seemingly innocuous or suspicious lesions.”4 Cytologic testing could be considered to help with clinical decision-making in rare cases where a patient declined a traditional biopsy; however, close clinical follow-up with repeat cytologic testing would be needed. Additionally, cytologic testing requires obtaining cells from the epithelial basal layer and is therefore technique sensitive, which can lead to false-negative results if not performed correctly. Cytologic testing could also be considered as a first-line approach for rural or resourcepoor areas where obtaining a traditional biopsy would not be feasible, but this is typically not a problem in the U.S.4 In general, intraoral visual and tactile exams followed by traditional incisional or excisional biopsy of suspicious lesions with histopathologic interpretation by a pathologist knowledgeable about the oral and maxillofacial complex is the gold standard for diagnosing oral potentially malignant disorders. Relying too heavily or exclusively on screening adjuncts, such as those listed above, could lead to missed and subsequently mismanaged premalignant and malignant disorders in some patients.

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Performing Oral Biopsies in Your Dental Office

In general, oral biopsies are well tolerated by patients, and biopsy sites typically show rapid healing with few complications. Despite this, there are multiple potential barriers that may prevent some dental professionals from performing biopsies in their offices. These include fear of medico-legal implications, lack of experience with obtaining biopsies, concerns about formulating a proper differential diagnosis and subsequently where to biopsy, apprehension about causing physical pain and mental anguish to the patient, difficulty interpreting the biopsy report and concerns about how to manage the patient depending on the diagnosis, especially in cases where oral cancer is identified.24 Given the litigious environment present within the U.S., medico-legal concerns by some providers may be valid, but are often overstated. The best way to avoid medico-legal issues is to not ignore intraoral lesions. The term “watchful neglect” has been used to describe instances where providers identify a seemingly innocuous intraoral lesion but then watch it, sometimes for years, without performing a biopsy or making a referral, even after the lesion begins to exhibit changes over time. While observation of benign-appearing intraoral lesions is certainly reasonable in some cases (e.g., to rule out resolving trauma), the observation period should be short, usually no more than two weeks, at which point a biopsy and/or referral to a specialist should be made for persistent lesions. This is especially true for lesions that have a broad differential diagnosis, such as intraoral white lesions, which can range from benign reactive changes to premalignant or even malignant disease.25 Caution must be taken when choosing not to biopsy seemingly benign intraoral lesions because if the provider’s working

clinical diagnosis is incorrect, this can potentially put the patient in significant peril. Additionally, non-biopsied intraoral lesions must be clinically followed closely, because even benign-appearing lesions can change over time and would therefore warrant biopsy to confirm the diagnosis. It should be emphasized that biopsy with histologic interpretation by a pathologist is the current standard of care for diagnosing any oral potentially malignant disorders. If there is ever doubt or question about the nature of an intraoral lesion, in this author’s opinion, a biopsy or referral to

The best way to avoid medico-legal issues is to not ignore intraoral lesions.

a specialist is preferable over long-term (i.e., greater than two weeks) watching and waiting. A biopsy can establish a baseline histopathologic diagnosis, which can ease patient anxiety, help inform how to best manage the patient moving forward and be used for comparison if future biopsies are obtained. Related to patient concerns centered on intraoral biopsies, Diamanti and colleagues performed a cross-sectional study of patients in the U.K. and found that 64% undergoing oral biopsy were primarily concerned about receiving a serious diagnosis such as cancer. Interestingly, only 6% were concerned about pain during and after the biopsy.24 Even though biopsies can be a bit nerve-wracking for some patients, this author has never had a single patient

upset or angry after receiving a benign diagnosis following biopsy. Oral health care professionals should also not fret if they do not entirely understand a diagnosis in a pathology report. If there is ever any question about any part of a pathology report, providers should always feel free to contact the pathologist who issued the report for further clarification and/or guidance. Working with an oral pathologist can be especially helpful in this regard because their training includes clinical management of patients with many different oral diseases, making them especially helpful in providing additional feedback about patient management. Similarly, oral medicine specialists can also be extremely helpful in this regard. In cases where there is a malignant diagnosis, such as squamous cell carcinoma, helping patients set up initial appointments with appropriate medical providers (e.g., a head and neck surgeon) can also be extremely helpful in minimizing patient anxiety and ensuring a smooth transition to the next stage of care. In general, oral health care practitioners should only undertake procedures that they feel comfortable and competent performing. General dentists and dental specialists are more than capable of performing oral biopsies; however, there is absolutely nothing wrong with referring to another specialist to perform the biopsy and/or manage the patient once a diagnosis has been made. In the study by Diamanti and colleagues, 39% of patients reported that they would feel anxious if their general dentist performed an intraoral biopsy, with only 23% feeling similarly anxious when the biopsy was performed in an oral medicine clinic. In either case, technical competence was the primary concern regardless of who performed the procedure.24 APRIL 2 0 2 1

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usually more worrisome for malignancy. The differential diagnosis for oral leukoplakia, erythroplakia and solitary chronic ulcers is broad, and these lesions almost always require biopsy to rule out the presence of oral epithelial dysplasia and/or malignancy such as squamous cell carcinoma. Microscopically, oral leukoplakia and erythroplakia may be 2A 2B characterized by hyperkeratosis, oral Figure Figure 2. Examples 2. Examples of oral of oral leukoplakia leukoplakia (A)(A) andand oraloral erythroplakia erythroplakia (B).(B). Biopsy Biopsy in (A) in (A) revealed revealed moderate moderate epithelial epithelialepithelial dysplasia and/or early squamous FIGURE S 2 . Examples of oral leukoplakia (2A ) and oral erythroplakia (2B ). Biopsy in (2A ) revealed moderate dysplasia dysplasia while while biopsy biopsy in (B) in (B) revealed revealed invasive invasive squamous squamous cellcell carcinoma. carcinoma. cell carcinoma or verrucous carcinoma. epithelial dysplasia while biopsy in (2B ) revealed invasive squamous cell carcinoma. Oral epithelial dysplasia is currently mild, moderate or severe carcinoma in situ.26,28 Erythroplakias are more likely this definition, a clinical diagnosis of oral Translating this into clinical practice, than leukoplakia to show high-grade leukoplakia is confirmed “… when any provider comfort and competence epithelial dysplasia or malignant changes aetiological cause other than tobacco/ along with open communication with at initial biopsy.26,28 Limited data show areca nut use has been excluded and patients are critical factors in deciding that about 2% of leukoplakias showing histopathology has not confirmed any whether to perform a biopsy yourself only hyperkeratosis without evidence of other specific disorder.”27 Similarly, or refer the patient to a specialist. erythroplakia refers to a red plaque dysplasia, 3% to 18% of mild/moderate Clinical Considerations for Oral with malignant potential and is defined dysplasias and up to 32% of severe oral Leukoplakia, Erythroplakia and equivalently to oral leukoplakia, with a dysplasias will progress to squamous cell Chronic Nonhealing Ulcers far lower reported prevalence of 0.02% carcinoma.29–33 Chronic ulcers often show 26 Oral potentially malignant disorders to 0.83% (FIGURE 2 ). Unfortunately, nonspecific changes microscopically, can present clinically in a variety of forms, many dental and medical professionals but as mentioned earlier can be and a comprehensive review is beyond the use these terms to broadly describe any associated with oral epithelial dysplasia scope of this article (see the corresponding intraoral white or red lesion, regardless and malignancy such as squamous cell article about oral potentially malignant of etiology and without consideration carcinoma. A critical point is that some disorders in this issue for an excellent for premalignant potential, which has leukoplakias, even without evidence review on this topic). Of these disorders, led to some confusion in the field. of oral epithelial dysplasia, may still oral leukoplakia is one of the more Regardless of how these terms are used to progress to cancer, making it essential common entities (relatively speaking) describe intraoral white and red lesions, that these patients be followed closely. and a source of consternation for many it is critical that the presence of either Patients diagnosed with oral epithelial oral health care providers (FIGURE 2 ). oral epithelial dysplasia (precancerous dysplasia typically require long-term Oral leukoplakia, which has a reported changes) or malignancy be excluded follow-up, periodic surveillance biopsies prevalence of 1% to 4% in Western histologically, as this could significantly and/or surgical excision of their lesions countries, is a clinical term that has been impact patient management. Similarly, depending on multiple factors including defined in various ways over the last oral ulcers, either solitary or multifocal, dysplasia grade, location, associated risk several decades and has generated some are also frequently encountered during factors and patient history.34 This includes confusion and occasional controversy routine intraoral exams and may be patients for which a clinical lesion has for clinicians and researchers.26 It is seen in the setting of oral leukoplakia or been entirely excised, because leukoplakia currently defined as a “… white plaque of erythroplakia. While multifocal ulcers is known to have recurrence rates ranging questionable risk having excluded (other) are often associated with autoimmune, from 5% to 49%, likely due in part to field known diseases or disorders that carry no autoinflammatory or infectious etiologies, cancerization effect.35–37 A mistake that 27 is sometimes made by oral health care solitary chronic ulcers (i.e., those generally increased risk for cancer.” According providers and other medical professionals lasting longer than two weeks) are to the consensus panel that developed 220 APRIL

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is to ignore or downplay a diagnosis of hyperkeratosis or dysplasia, especially mild and moderate grades of disease, because no evidence of malignant transformation was identified in the initial biopsy. This can lead patients to not entirely understand the significance of their diagnosis and the need for long-term clinical follow-up with an oral health care provider. It is critical that dental professionals clearly explain to patients the increased risk of malignant transformation associated with a diagnosis of oral dysplasia as well as the need for life-long, long-term clinical follow-up. Similarly, a diagnosis of hyperkeratosis from oral leukoplakia does not imply a completely benign process and should be approached by dental professionals with caution. As stated earlier, a small percentage of oral leukoplakias showing only hyperkeratosis histologically without evidence of dysplasia will still progress to malignancy.29 Recent work by Villa and colleagues showed that some oral leukoplakias showing only hyperkeratosis harbored similar genetic mutations as leukoplakias with histologic evidence of epithelial dysplasia.38 They referred to these lesions as “keratosis of unknown significance,” a clinical term used to describe lesions showing hyperkeratosis histologically, but for which a clinical source of chronic trauma leading to hyperkeratosis cannot be identified.38 A prudent approach for any dental professional who receives a diagnosis of hyperkeratosis following biopsy is to try and ascertain the source of trauma or other causes that could lead to hyperkeratotic white changes in the affected area. If no such source can be identified, then continued, close clinical follow-up is recommended, with additional surveillance biopsies as needed. Additionally, it is always advised to correlate clinical findings with biopsy results from a pathology report. If biopsy

results do not make sense or correlate with what is seen clinically, providers should consult with the pathologist who issued the report, consider taking additional biopsies and/or refer the patient to a specialist for a second opinion. In general, any white or red soft tissue changes or chronic ulcer concerning for an oral potentially malignant disorder should be biopsied immediately. This is especially true if these lesions are located at anatomic sites known to be at higher risk for malignant transformation such as the

The threshold for performing a biopsy should be lower in patients with known risk factors associated with oral cancer.

lateral/ventral tongue and floor of mouth.29 Furthermore, the threshold for performing a biopsy should be lower in patients with known risk factors associated with oral cancer. These include tobacco use, betel quid use, heavy alcohol use, gender (oral cancers are about twice as common in men), individuals older than 55, heavy ultraviolet light exposure to the lips and face, poor nutrition, immunocompromised state (e.g., solid organ transplant, HIV/AIDS, etc.), history of chronic graft-versushost disease following hematopoietic stem cell transplantation and genetic syndromes such as Fanconi anemia and dyskeratosis congenita that predispose patients to developing oral cancer.39 If trauma or infection are on the

differential diagnosis and observation or some type of treatment is initiated (e.g., smoothing out of adjacent sharp cusps, treatment with antifungal medication, etc.), a general guideline recommended by this author is that lesions that persist beyond two weeks should be biopsied to confirm the diagnosis and to rule out premalignant or malignant changes. Additionally, oral leukoplakias and erythroplakias can be heterogeneous histologically, meaning that different grades of dysplasia and even malignant changes may be present simultaneously in different areas of the same clinical lesion. This possibility further supports the need for obtaining multiple biopsies in large lesions, especially those with a heterogeneous clinical appearance and for close clinical follow-up of mild and moderate dysplastic lesions where surgical excision is not indicated due to the potential for high patient morbidity. Clearly, every patient scenario is different and clinical judgment should be exercised to determine the most appropriate clinical recommendations and course of action for each patient.

Final Thoughts and Key Recommendations

Extra- and intraoral cancer screenings have the potential to save lives and should be part of every dental exam. They are easy to perform, can be integrated well with current COE and POE workflows and further build trust between patients and providers. Additional research is needed to evaluate the effects that visual and tactile extra- and intraoral exams have on reducing oral cancer rates, patient morbidity and cancer-related mortality. Dental professionals are uniquely positioned to expertly perform these screenings and bolster their roles as oral health care providers focused on patients’ oral health and potentially saving lives. APRIL 2 0 2 1

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Key recommendations: ■ Extra- and intraoral screening exams for oral potentially malignant disorders and oral cancer should be performed at every COE and POE. ■ Providers should rely primarily on visual and tactile intraoral exams because there is currently no strong evidence supporting the broad use of adjuncts in routine oral cancer screening. ■ Suspected oral potentially malignant disorders should be biopsied immediately in order to rule out the presence of oral epithelial dysplasia and cancer. ■ Not all oral leukoplakias will show oral epithelial dysplasia when biopsied, but may still have premalignant potential (e.g., keratosis of unknown significance). ■ Patients with a diagnosis of oral epithelial dysplasia require long-term clinical follow-up. ■ If a lesion persists longer than two weeks following treatment or observation, biopsy should strongly be considered to confirm the diagnosis and help guide management. ■ Always consider referral to a specialist for a second opinion and/ or management of oral potentially malignant disorders, if needed. n RE FEREN CE S 1. American Cancer Society. 2020 Cancer Estimates. www. cancer.org/cancer/oral-cavity-and-oropharyngeal-cancer/ about/key-statistics.html. Accessed Oct. 24, 2020. 2. SEER Database. seer.cancer.gov/statfacts/html/oralcav.html. Accessed Feb. 11, 2020. 3. Chi AC, Day TA, Neville BW. Oral cavity and oropharyngeal squamous cell carcinoma — an update. CA Cancer J Clin Sep–Oct 2015;65(5):401–21. doi: 10.3322/ caac.21293. Epub 2015 Jul 27. 4. Lingen MW, et al. Evidence-based clinical practice guideline for the evaluation of potentially malignant disorders in the oral cavity: A report of the American Dental Association. J Am Dent Assoc 2017 Oct;148(10):712–727.e10. doi: 10.1016/j. adaj.2017.07.032. 5. McDermott JD, et al. Elderly Black non-Hispanic patients with head and neck squamous cell cancer have the worst survival outcomes. J Natl Compr Canc Netw 2020 Sep 28;1–11. doi:

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10.6004/jnccn.2020.7607. Online ahead of print. 6. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017 Jan;67(1):7–30. doi: 10.3322/ caac.21387. Epub 2017 Jan 5. 7. Siu AL. U.S. Preventive Services Task Force. Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2016 Feb 16;164(4):279–96. doi: 10.7326/M15-2886. Epub 2016 Jan 12. 8. Doubeni CA, et al. Effectiveness of screening colonoscopy in reducing the risk of death from right and left colon cancer: A large community-based study. Gut 2018 Feb;67(2):291–298. doi: 10.1136/gutjnl-2016-312712. Epub 2016 Oct 12. 9. U.S. Preventive Services Task Force, et al. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. JAMA 2018 Aug 21;320(7):674–686. doi: 10.1001/jama.2018.10897. 10. Brocklehurst PR, Speight PM. Screening for mouth cancer: The pros and cons of a national programme. Br Dent J 2018 225(9):815–819. doi.org/10.1038/sj.bdj.2018.918. 11. Moyer VA. U.S. Preventive Services Task Force. Screening for oral cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014 Jan 7;160(1):55–60. doi: 10.7326/M13-2568. 12. Sankaranarayanan R, et al. Effect of screening on oral cancer mortality in Kerala, India: A cluster-randomised controlled trial. Lancet 2005 Jun 4–10;365(9475):1927–33. doi: 10.1016/S0140-6736(05)66658-5. 13. Brocklehurst P, et al. Screening programmes for the early detection and prevention of oral cancer. Cochrane Database Syst Rev 2010 Nov 10;(11):CD004150. doi: 10.1002/14651858.CD004150.pub3. 14. American Dental Association: Cancer (head and neck). www.ada.org/en/member-center/oral-health-topics/cancerhead-and-neck. Accessed Sept. 27, 2020. 15. American Academy of Oral Medicine: Oral cancer screening. www.aaom.com/clinical-practice-statement--oralcancer-screening. Accessed Sept. 27, 2020. 16. Walsh T, et al. Clinical assessment to screen for the detection of oral cavity cancer and potentially malignant disorders in apparently healthy adults. Cochrane Database Syst Rev 2013 Nov 21;2013(11):CD010173. doi: 10.1002/14651858.CD010173.pub2. 17. Gupta A, Sonis S, Uppaluri R, Bergmark RW, Villa A. Disparities in oral cancer screening among dental professionals: NHANES 2011–2016. Am J Prev Med 2019 Oct;57(4):447–457. doi: 10.1016/j.amepre.2019.04.026. Epub 2019 Aug 20. 18. National Institute of Dental and Craniofacial Research: The concise oral exam. www.nidcr.nih.gov/research/conducted-atnidcr/clinical-director/oral-exam. Accessed Sept. 27, 2020. 19. University of Toronto Faculty of Dentistry: Extraoral and intraoral soft tissue examination. iits.dentistry.utoronto.ca/extraoraland-intraoral-soft-tissue-examination. Accessed Sept. 27, 2020. 20. Awojobi O, Scott SE, Newton T. Patients’ perceptions of oral cancer screening in dental practice: A cross-sectional study. BMC Oral Health 2012 Dec 18;12:55. doi: 10.1186/1472-6831-12-55. 21. Lubin JH, et al. Total exposure and exposure rate effects for alcohol and smoking and risk of head and neck cancer: A pooled analysis of case-control studies. Am J Epidemiol 2009 Oct 15;170(8):937–47. doi: 10.1093/aje/kwp222. Epub 2009 Sep 10. 22. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol Apr–May 2009;45(4– 5):309–16. doi: 10.1016/j.oraloncology.2008.06.002. Epub 2008 Sep 18. 23. Timbang MR, et al. HPV-related oropharyngeal cancer: A review on burden of the disease and opportunities for prevention and early detection. Hum Vaccin Immunother 2019;15(7–8):1920–1928. doi: 10.1080/21645515.2019.1600985. Epub 2019 May 7. 24. Diamanti N, Duxbury AJ, Ariyaratnam S, Macfarlane

TV. Attitudes to biopsy procedures in general dental practice. Br Dent J 2002 May 25;192(10):588–92. doi: 10.1038/ sj.bdj.4801434. 25. Jones KB, Jordan R. White lesions in the oral cavity: Clinical presentation, diagnosis and treatment. Semin Cutan Med Surg 2015 Dec;34(4):161–70. doi: 10.12788/j.sder.2015.0180. 26. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. WHO Classification of Head and Neck Tumors. 4th ed. IARC: Lyon; 2017. 27. Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med 2007 Nov;36(10):575–80. doi: 10.1111/j.16000714.2007.00582.x. 28. Woo SB. Oral epithelial dysplasia and premalignancy. Head Neck Pathol 2019 Sep;13(3):423–439. doi: 10.1007/ s12105-019-01020-6. Epub 2019 Mar 18. 29. Chaturvedi AK, et al. Oral leukoplakia and risk of progression to oral cancer: A population-based cohort study. J Natl Cancer Inst 2020 Oct 1;112(10):1047–1054. doi: 10.1093/jnci/djz238. 30. Mehanna HM, Rattay T, Smith J, McConkey CC. Treatment and follow-up of oral dysplasia — a systematic review and meta-analysis. Head Neck 2009 Dec;31(12):1600–9. doi: 10.1002/hed.21131. 31. Silverman S, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer 1984 Feb 1;53(3):563–8. doi: 10.1002/1097-0142(19840201)53:3<563::aidcncr2820530332>3.0.co;2-f. 32. Brouns E, et al. Malignant transformation of oral leukoplakia in a well-defined cohort of 144 patients. Oral Dis 2014 Apr;20(3):e19–24. doi: 10.1111/odi.12095. Epub 2013 Mar 25. 33. Schepman KP, van der Meij EH, Smeele LE, van der Waal I. Malignant transformation of oral leukoplakia: A follow-up study of a hospital-based population of 166 patients with oral leukoplakia from The Netherlands. Oral Oncol 1998 Jul;34(4): 270–275. 34. Villa A, Woo SB. Leukoplakia — a diagnostic and management algorithm. J Oral Maxillofac Surg 2017 Apr;75(4):723–734. doi: 10.1016/j.joms.2016.10.012. Epub 2016 Oct 26. 35. Angadi PV, Savitha JK, Rao SS, Sivaranjini Y. Oral field cancerization: Current evidence and future perspectives. Oral Maxillofac Surg 2012 Jun;16(2):171–80. doi: 10.1007/ s10006-012-0317-x. Epub 2012 Feb 22. 36. Kuribayashi Y, Tsushima F, Sato M, Morita KI, Omura K. Recurrence patterns of oral leukoplakia after curative surgical resection: Important factors that predict the risk of recurrence and malignancy. J Oral Pathol Med 2012 Oct;41(9):682–8. doi: 10.1111/j.1600-0714.2012.01167.x. Epub 2012 Jun 15. 37. Sundberg J, et al. Recurrence rates after surgical removal of oral leukoplakia — a prospective longitudinal multi-centre study. PLoS One 2019; 14(12):e0225682. doi: 10.1371/journal. pone.0225682. 38. Villa A, et al. Oral keratosis of unknown significance shares genomic overlap with oral dysplasia. Oral Dis 2019 Oct;25(7):1707–1714. doi: 10.1111/odi.13155. Epub 2019 Jul 23. 39. American Cancer Society. Risk Factors for Oral Cavity and Oropharyngeal Cancers. www.cancer.org/cancer/oral-cavityand-oropharyngeal-cancer/causes-risks-prevention/risk-factors. html. Accessed Sept. 27, 2020. T HE AU T HOR , Kyle Jones, DDS, PhD, can be reached at Kyle.Jones@ucsf.edu.

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A Guide for Dental Practitioners of Common Oral Potentially Malignant Disorders Diana Wang, DDS; Shaiba Sandhu, BDS, DDS; and Sook-Bin Woo, DMD

abstract Background: Squamous cell carcinoma is the most common malignancy in the oral cavity and typically arises from a group of precancerous lesions known as oral potentially malignant disorders. Types of studies reviewed: A comprehensive review of literature was completed by searching the PubMed electronic database using a combination of search terms: oral potentially malignant disorders, leukoplakia, proliferative verrucous leukoplakia, erythroplakia, oral lichen planus, actinic cheilitis, smokeless tobacco keratosis, oral submucous fibrosis and palatal lesions associated with reverse smoking. Results: Oral leukoplakia, proliferative leukoplakia, erythroleukoplakia and submucous fibrosis are the lesions highly associated with the development of oral cancer. Many cases of leukoplakia may not show dysplasia on biopsy, but molecular studies suggest that they already harbor mutations and as such should be evaluated and managed as a precancerous lesion. Risk factors beyond smoking and tobacco, such as immunosuppression, history of cancer and others, are reviewed. Conclusion: Dentists may be the first to encounter such lesions and therefore play an important role in diagnosing and managing these conditions. Practical implications: The goal of this review is to provide an updated and simple reference for dentists to guide them in lesion identification, diagnosis and, in some cases, treatment. Key words: Oral potentially malignant disorders, leukoplakia, erythroleukoplakia, oral squamous cell carcinoma

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Risk Factors for Leukoplakia, Erythroplakia and Erythroleukoplakia Risk factors* Smoking Alcohol AUTHORS Diana Wang, DDS, is a fourth-year and current oral and maxillofacial pathology co-chief resident at the Harvard Dental School of Medicine and is pursuing a DMSc in oral biology. Her research lies in the epigenetic regulation of wound healing and oral squamous cell carcinoma and melanoma progression. Conflict of Interest Disclosure: None reported. Shaiba Sandhu, DDS, is the current oral medicine chief resident at the Harvard School of Dental Medicine and the Brigham and Women’s Hospital/ Dana Farber Cancer Institute. Conflict of Interest Disclosure: None reported.

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Sook-Bin Woo, DMD, MMSc, is an associate professor in the department of oral medicine, infection and immunity and the oral and maxillofacial pathology program director at the Harvard School of Dental Medicine. She also practices as an oral medicine specialist at the Brigham and Women’s Hospital/Dana Farber Cancer Institute. Dr. Woo is a fellow of dental surgery of the Royal College of Surgeons. Conflict of Interest Disclosure: None reported.

ral potentially malignant disorders have a broad spectrum of clinical presentations and are considered precancerous lesions at risk for transforming into oral squamous cell carcinoma. Dentists may be the first to encounter such lesions and therefore play an important role in diagnosing and managing these conditions. The goal of this review is to provide an updated and simple reference for dentists to guide them in lesion identification, diagnosis and, in some cases, treatment. Oral squamous cell carcinoma (OSCC) is the most common malignancy in the oral cavity constituting over 90% of all oral cancers. OSCC, as with all other malignant epithelial tumors such as breast, colon, lung and prostate cancers, occurs as a result of sequential accumulation of mutations arising from a single or just a few clones of mutated cells. Some of the mutations occur sporadically (especially in older patients from miscoding of DNA), while others arise from exposure to environmental carcinogens such as tobacco, alcohol, areca nut, human papillomavirus (HPV) and ultraviolet radiation (for lip cancers). Because OSCC results from cumulative mutations, it therefore logically follows that all precancerous lesions that precede OSCC must arise from mutations, and the risk factors for precancerous lesions are the same as for OSCC. Just as important, an active immune system destroys tumor cells as they develop. Immunocompromised patients on cancer treatment or long-term immunosuppressive therapy or elderly patients with immunosenescence are at a higher risk for developing cancer (TA BLE 1 ).

Areca nut Immunosuppression Autoimmune disease Personal history of cancer Family history of cancer Human papillomavirus infection Older age (immunosenescence) Chronic ultraviolet radiation exposure Genetic diseases such as dyskeratosis congenita

The overall five-year survival rate for OSCC is 66%; however, this rate is 85% for local disease and 40% for those with distant metastases.1 As such, early detection of cancer, while the disease is still localized, provides the best chance of disease-free survival. Even more important, early detection and removal of the precancerous lesion may prevent the development of cancer altogether.2 Oral potentially malignant disorders (OPMDs) as classified by the World Health Organization (WHO) consist of 12 entities that are deemed precancerous lesions or conditions that are at risk of malignant transformation to OSCC.3 However, their propensity to develop OSCC varies considerably because they are a heterogeneous group of lesions.

Leukoplakia/Proliferative Leukoplakia Leukoplakia is the most common OPMD worldwide with a pooled global prevalence of 4.11%.4 The WHO defines leukoplakia as “a white plaque of questionable risk, having excluded other known diseases or disorders that carry no increased risk for cancer.”5 It is a clinical term used for describing a usually asymptomatic white plaque that is associated with an increased risk of exhibiting or subsequently developing dysplasia/ OSCC and therefore excludes other white plaques that occur secondary

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to immune-mediated, inflammatory, traumatic/frictional or infectious causes.

Clinical Findings

Most leukoplakia lesions occur in the fourth to seventh decade of life.6 Unifocal leukoplakia is more common in males, with the ventral tongue and floor of the mouth being the most common locations.6,7 Leukoplakia is classified into homogenous and nonhomogenous types. Homogenous leukoplakia appears as a well-delineated (at least in part) white plaque that is “uniformly flat, thin and exhibits shallow cracks of the surface keratin” (FIGURE 1 A ).5 Nonhomogenous leukoplakia, on the other hand, may present with a verrucous (corrugated) nodular or speckled appearance (irregular white and red patches) (FIGURE 1B ).5 It is important that all such lesions be palpated for firmness or induration, which is often noted in OSCC. Proliferative (verrucous) leukoplakia (PL) is an aggressive, persistent, recurrent form of nonhomogenous leukoplakia commonly diagnosed in the sixth to seventh decade of life with a femalemale ratio of about 5:1 and a weak association with tobacco use.8–11 PL is characterized by keratotic plaques that may appear smooth, fissured or verrucous with or without erythema/ulceration.11,12 It commonly affects the gingiva, buccal mucosa and tongue and slowly but relentlessly spreads over time.8,10,11 PL may be multifocal (FIGURES 2A and 2B ) or may present as a single large lesion greater than 4.0 cm involving one site or a single large lesion greater than 3.0 cm involving contiguous sites (FIGURE 2C ).11 It is important for clinicians to recognize the differences between a true leukoplakia and benign keratotic lesions such as morsicatio mucosae oris (MMO)

FIGURE S 1. Homogenous leukoplakia: sharply demarcated white plaque on the left ventral tongue (1A ). Nonhomogenous leukoplakia: primarily well-demarcated predominantly white fissured plaque with focal erythema on the right lateral border of the tongue (1B ).

and benign alveolar ridge keratosis (BARK) that are caused by frictional trauma from mastication, parafunctional habits or food impaction.13,14 MMO commonly occurs on the buccal mucosa, lower lip mucosa and lateral border of the tongue (FIGURES 3A and 3B ), while BARK is frequently seen on the retromolar pad (often bilaterally) and the edentulous ridge (FIGURE 3C ).15,16 These common chronic frictional keratotic lesions present as poorly delineated, irregular, shaggy, whitishgray or white papules and plaques on oral sites easily accessible to frictional injury.13,14 Lesions of MMO in particular wax and wane in size over time.

Malignant Transformation

At the initial biopsy, approximately 55% of leukoplakia lesions show hyperkeratosis without dysplasia and the remaining 45% show dysplasia/ OSCC (10% with verrucous hyperplasia, 31% with mild dysplasia, 24% with moderate dysplasia, 15% with severe dysplasia/carcinoma in situ and 20% with SCCa).17 The overall malignant transformation of leukoplakia reported in the literature ranges from 3.7%18 to 40.8%,19 with a recent meta-analysis of 32 studies including 23,489 patients estimating a mean malignant transformation rate of 9.70%.20 The presence of epithelial dysplasia is considered one of the important risk factors predisposing to malignant transformation.21 However,

it is important to note that leukoplakia without obvious dysplasia is associated with the risk of transformation of oral leukoplakia to invasive OSCC in 15% to 30% of cases.8,11,22,23 The anatomical location of oral leukoplakia has also been shown to influence this risk, with the floor of the mouth and ventral tongue being common sites that are most likely to show severe dysplasia or OSCC at the time of biopsy.3,17,23 Additionally, the size of the leukoplakia appears to have an impact, with lesions larger than 2 cm2 exhibiting a fivefold higher risk of malignant transformation.15,22 An association between older age and the risk of malignant transformation has shown a higher risk among those over age 50.21 In general, nonhomogeneous leukoplakia carries approximately four- to sevenfold greater risk of malignant transformation as compared to homogeneous lesions.3,15 Among the nonhomogenous leukoplakia lesions, PL has the highest malignant transformation rate of 65% to 100%.10,16 As such, all lesions of leukoplakia must be biopsied, and multiple biopsies should be performed if lesions are nonhomogenous. There is a subset of leukoplakias caused by human papillomavirus (HPV) with a 15% malignant transformation rate.24 HPV is responsible for 5% of OSCC and 70% to 80% of squamous cell carcinomas in the oropharynx especially in the tonsils.25–27 APRIL 2 0 2 1

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FIGURE S 2 . Proliferative leukoplakia, nonhomogenous type: multiple, partially to well-demarcated, thin-to-thick, fissured, white plaques and erythematous macules of the tongue dorsum (2A ); demarcated white plaque involving the mandibular anterior gingiva, vestibule and lip mucosa (2B ; same patient as 2A ); and contiguous welldemarcated thick, fissured white plaques involving the left buccal mucosa, mandibular vestibule and buccal gingiva (2C ). (Images courtesy of Dr. Nathaniel Treister.)

FIGURE S 3 . Frictional keratosis: morsicatio mucosae oris (3A ) with shaggy, white, macerated surface of the right buccal mucosa and (3B ) left buccal mucosa in one patient. Benign alveolar ridge (frictional) keratosis: poorly demarcated, wrinkled white lesion on the left retromolar pad (3C ).

Adjunctive Diagnostic Tests

Several adjunctive tests are available and may help a clinician identify the most appropriate biopsy sites. Toluidine blue is a metachromatic dye that is used as a vital stain to highlight dysplasia/carcinoma in leukoplakias.28,29 A positive test is when the blue dye is retained by the tissue after toluidine blue application and subsequent decolorization with acetic acid.28,29 The hypothesis explaining the positive uptake includes the high density of nuclear material, the loss of cell cohesion and increased mitoses in the dysplastic/ malignant lesions.30 However, there may be false-positive staining in inflammatory lesions and false-negative staining in many leukoplakias because of the thick keratin layer, limiting its use.29,30 Light-based adjuvant diagnostic techniques, including chemiluminescence and tissue autofluorescence, work on the premise that dysplastic and neoplastic 226 APRIL

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lesions have abnormal metabolic/ structural changes that cause different absorbance and reflectance properties on exposure to specific wavelengths of light.31 Dysplastic epithelium when subjected to chemiluminescence (e.g., ViziLite, ViziLite Plus, MicroLux/DL) appear distinctly white (acetowhite) and when subjected to autofluorescence (e.g., VELscope) appear darker compared to the normal epithelium.28 High equipment costs, lack in the consistency of the technique and the inability to objectively measure visualization results are some of the limitations of these optical imaging techniques.28 Narrow band imaging (NBI) is an optical imaging technology that utilizes an endoscope and varying wavelengths of light to enhance the mucosal surface texture and underlying blood vessels.32 NBI utilizes a mode in which blue light (400–430 nm) and green light (525–555 nm) are emitted simultaneously, resulting

in varied patterns of brown-colored superficial vasculature and cyancolored deep vasculature, respectively.32 Dysplastic and cancerous lesions have been classified into four patterns of intrapapillary capillary loop (IPCL) morphology such as parallel and perpendicular (Type 1), dilated (Type II), elongated or tangled (Type III) and large vessels with IPCL destruction (Type IV), with Type III and Type IV most strongly correlated with dysplasia and OSCC, respectively.33 The sensitivity and specificity of detecting OSCC is 95% and 97%, respectively.34 However, NBI is costly and there is variability when interpreting microvasculature patterns among NBI users.

Management

There is controversy regarding whether lesions of leukoplakia without dysplasia or with mild dysplasia should be excised. However, because these are mutated

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lesions, it is reasonable to excise them if the patient is amenable to surgery. Most leukoplakias are managed by oral and maxillofacial surgeons, although oral medicine specialists, periodontists or even general dentists may perform excisions or laser ablations for leukoplakias with or without mild dysplasia if they have experience doing so. Moderate and severe epithelial dysplasia or carcinoma in situ is usually managed by an oral medicine specialist, oral and maxillofacial surgeon or head and neck surgeon and requires scalpel excision for evaluation of margins because these may already harbor invasive OSCC. Laser ablation and cryosurgery do not allow for tissue evaluation and are therefore not the treatment of choice.35 For multifocal PL, complete excision of all the lesions with adequate margins is generally not possible, and even after “complete excision,” there is a 71.2% rate of recurrence.21 Nonsurgical approaches using natural and systemic chemical agents such as carotenoids (beta carotene, lycopene), retinoids, polyphenols (curcumin, green tea polyphenols) or topical bleomycin have been utilized, but to date, there is no conclusive evidence to support the effectiveness of these agents in preventing malignant transformation.35 Leukoplakia with a histopathologic diagnosis of OSCC requires complete excision, and patients may need to be referred to a head and neck oncologist for surgery, radiation therapy, chemotherapy or multimodality therapy depending upon the stage.35 Additionally, patients must be counseled to discontinue/ avoid exposure to environmental risk factors (such as tobacco use, betel chewing and alcohol abuse) and should continue with close surveillance

FIGURE 4 . Erythroplakia: well-delineated, homogenous, red plaque on the right lateroposterior tongue. (Image courtesy of Dr. Alessandro Villa.)

FIGURE 5 . Actinic cheilitis: atrophy/pallor and

and periodic monitoring (every three to six months) because of the risk of recurrence and development of a second primary OSCC.

Malignant Transformation

Erythroplakia

In comparison to leukoplakia, erythroplakia is rare with an estimated global prevalence of approximately 0.17%.4 It is defined by the WHO as “a fiery red patch that cannot be characterized clinically or pathologically as any other definable disease.”36 Erythroplakia is a clinical term only that is used to describe an erythematous lesion, which is usually asymptomatic and cannot be attributed to vascular, inflammatory, infectious or traumatic/frictional causes.37

Clinical Findings

Erythroplakia is predominantly found in the sixth to seventh decade of life and has a slight male predilection.38,39 Any oral mucosal surfaces may be involved, but the soft palate, floor of the mouth and buccal mucosa are most commonly affected.22,40 Erythroplakia is characterized as a well-demarcated, flat or slightly elevated/nodular, velvety red plaque that is usually asymptomatic (FIGURE 4 ).37 However, it can sometimes present as a mixed red and white lesion, in which case it is referred to as erythroleukoplakia or speckled leukoplakia, a form of nonhomogeneous leukoplakia (see leukoplakia above).5

erythema with loss of delineation between the lower lip vermillion and skin. (Image courtesy of Dr. Nathaniel Treister.)

Erythroplakia typically presents histologically as severe epithelial dysplasia, carcinoma in situ or OSCC in at least 90% of cases at the time of biopsy.37,40 Although erythroplakia is not very common, its malignant transformation rate is 45% to 65%, one of the highest among the OPMDs.4,40,41

Treatment

Because of the high risk of malignant transformation, surgical excision with clear margins is the treatment of choice.35,42 Lifetime monitoring is recommended owing to the risk of recurrence, with a recent study showing five times increased risk of recurrence of erythroplakia or OSCC if the size of erythroplakia exceeds 0.8 cm2.42

Actinic Cheilitis

Actinic keratosis is a precancerous epidermal lesion caused by prolonged UV light exposure on the skin of the head and neck region and upper extremities in the elderly in the seventh to ninth decade.43 It typically presents as well-demarcated erythematous, scaly patches in sunexposed areas.43 Diffuse changes on the lip vermillion caused by chronic UV light exposure is known as actinic cheilitis.

Clinical Findings

Actinic cheilitis frequently occurs in fair-skinned male adults in the fifth to seventh decade, with 97% of APRIL 2 0 2 1

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contactants (such as dental amalgam) tend to be unilateral.56,57 Patients with autoimmune diseases such as lupus erythematosus and chronic graft-versushost disease after hematopoietic stem cell transplant have similar-appearing lesions. Recent studies have shown a statistically significant correlation between oral LP and thyroid disease, the use of levothyroxine or both.58

Clinical Findings

FIGURE S 6 . Oral lichen planus: reticular lichen planus exhibiting diffuse white symmetrical reticulations with variable erythema on the right and left buccal mucosa (6A and 6B ). Erosive lichen planus: erythematous, desquamative gingivitis of the maxillary and mandibular gingiva with faint white changes (6C ). Ulcerative lichen planus: ulceration with yellow fibrinous membrane (arrow) surrounded by erythema and white striations of the right buccal mucosa, with involvement of the right palatal gingiva (6D ). (Image 6D courtesy of Dr. Herve Sroussi.)

these lesions occurring on the lowerlip vermilion.44–46 It appears as diffuse, atrophic areas or shallow erosions on the lip with the blurring of the lip vermilion-skin interface (FIGURE 5 ).45,46 Often, a discrete actinic keratosis will arise within actinic cheilitis.

Malignant Transformation

Similar to leukoplakia discussed above, actinic cheilitis is considered a precursor to OSCC with 87.5% exhibiting a histological spectrum of epithelial dysplasia (52% with mild dysplasia, 23% with moderate dysplasia and 12.5% with severe dysplasia).45 The malignant transformation rate ranges from 1.2%45 to 3.2%,47 which is a much lower rate than intraoral precancerous lesions.

Treatment

Incisional biopsy provides a definitive diagnosis for management. OSCCs are treated with excision. In the past, actinic cheilitis with epithelial dysplasia 228 APRIL

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was treated with vermilionectomy. Current therapy is with topical 5-fluorouracil or imiquimod.48,49

Lichen Planus

Lichen planus (LP) is a chronic, immune-mediated mucocutaneous disorder that affects the skin, nails and oral and genital mucosa.50–52 Oral LP has a global prevalence between 0.1% and 3.2%53 and has been linked to the hepatitis C virus, with Italian patients exhibiting a higher incidence of HLA-DR6.54 Familial oral LP has also been reported to have a higher incidence of HLA-A alleles, suggesting a genetic predisposition. Although the etiology of oral LP remains unknown, the final common pathway in LP leads to T-cell destruction of the basal epithelial cells.55 Idiopathic oral LP is indistinguishable from LP that is caused by medications (such as hydrochlorothiazide and levothyroxine) and are generally bilateral. On the other hand, oral lichenoid lesions caused by

Oral LP occurs in adults in the fourth to fifth decade with a female predilection.53 The major presentations are reticular/keratotic, erythematous/ erosive and ulcerative.51 Reticular LP presents usually as asymptomatic or mildly symptomatic, interlacing white striations (Wickham striae) with an erythematous background commonly affecting the buccal mucosa, gingiva and tongue bilaterally and less frequently the hard palatal and lip mucosa (FIGURES 6 A and 6B ).51 Erosive LP presents as painful, erythematous and diffuse desquamative gingivitis but may also be seen as a background to Wickham striae (FIGURE 6C ).51 Ulcerative LP is usually painful and presents as expected, as an ulcer with yellow fibrin membrane (FIGURE 6D ). Other subtypes include the atrophic LP best seen as white, smooth, depapillated areas on the dorsum of tongue. Oral bullous LP is rarely seen because bullae breakdown rapidly to form erosive LP. The existence of plaquetype LP is under dispute, and solitary white plaque on the ventral tongue without any striations is best classified as leukoplakia even if the histopathology shows “lichenoid mucositis.” Oral LP occurs concomitantly with extraoral disease, in which vaginal/ vulvar or cutaneous involvement occurs in 19% and 16% of cases, respectively.52 Gingival and genital involvement in

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TABLE 2

Topical Corticosteroids in Descending Order of Potency Class I

Clobetasol propionate 0.05% gel/cream/ointment Betamethasone dipropionate 0.05% gel/cream/ointment

women is known as vulvovaginal-gingival (VVG) syndrome, with 15% of the reported cases exhibiting buccal mucosal fibrosis.52,59 A penile-oral form of LP also exists, and as such, the term genitalgingival syndrome is more accurate.60 It is important for practicing dentists to query patients regarding other sites of LP involvement, as oral lesions in genitalgingival syndrome are often refractory to topical corticosteroid therapy.59

Class II

Fluocinonide 0.05% gel/cream/ointment Betamethasone dipropionate 0.05% cream/ointment Budesonide 0.025% cream

Class III

Triamcinolone 0.1% dental paste/cream/ointment

Class IV

Fluocinolone acetonide 0.025% ointment

Class V

Desonide 0.05% ointment (for lips)

Class VI

Desonide 0.05% cream Fluocinolone acetonide 0.01% cream

Malignant Transformation

LP has been associated with a 0.4% to 1.4% malignant transformation rate.61,62 Treatment of “plaque-type” LP (likely leukoplakia that may already be dysplastic) with corticosteroids may lead to the development of dysplasia and OSCC. Biopsies should be performed on demarcated white plaques or leukoplakias that develop within lesions of oral LP especially if they occur on the ventral tongue or floor of the mouth, which are high-risk sites for dysplasia or OSCC. In some cases, red and white lesions diagnosed as LP are in actuality erythroleukoplakias, which have a high rate of malignant transformation.

Treatment

In general, reticular LP is usually asymptomatic and requires no treatment. On the other hand, symptomatic oral LP regardless of the type is treated with topical corticosteroids (TA BLE 2 ). Diffuse oral lesions are often treated with dexamethasone rinses 0.1mg/ml (swish for five minutes, three to four times/day) while localized lesions are managed with corticosteroid gels/creams such as fluocinonide and clobetasol, applied two to four times a day.63–65 Patients should not eat or drink for 20 minutes after application to allow for the steroid to stay in place and be absorbed. Triamcinolone dental paste has a gritty

FIGURE S 7. Management of oral lichen planus: application of gauze saturated with topical steroid on the gingiva (7A ); custom-made trays for the delivery of topical steroids (7B ).

consistency and is not appropriate for use in diffuse lesions, although triamcinolone gel or cream may be used. Lesions on the gingiva can be effectively treated by applying the corticosteroid onto a strip of gauze or in a custom tray for 20 minutes two to three times/day (FIGURES 7A and 7B ). Patients with generalized gingival involvement of OLP should practice good oral hygiene, as the inflammatory response to plaque and oral biofilm may exacerbate lesions.66 Prednisone is often prescribed to bring severe and extensive disease under control rapidly so that topical corticosteroids can work more effectively. Patients with oral LP refractory to topical steroids are often treated with immunomodulatory drugs such as hydroxychloroquine, azathioprine, cyclosporine or mycophenolate mofetil.67–69 Such drugs require

monitoring for side effects and are best prescribed by a specialist. Lastly, patients with cutaneous or genital LP should be referred to dermatologists for appropriate management.

Smokeless Tobacco Keratosis

In the United States, an estimated 47.4 million adults currently use tobacco products.70 Although there has been a decline in smoking prevalence within the U.S and European countries recently,71 2.1% of the U.S. population uses a noncombusted form of tobacco known as smokeless tobacco (ST).70 On the other hand, ST is more commonly used than cigarettes in Southeast Asia.72 There are two forms of ST used in Western countries, chewing tobacco and snuff, while other forms of ST exist in the Middle East (such as shammah, maras and nass) and North APRIL 2 0 2 1

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FIGURE 8 . Smokeless tobacco keratosis: poorly demarcated, grayish-white edematous lesion with fissures and parallel ridges in the mandibular vestibular mucosa.

FIGURE 9. Oral submucous fibrosis, late stage: blanching of the soft palate and bilateral tonsillar fauces with concomitant uvular atrophy. (Image courtesy of Drs. Chandramani B. More and Naman R. Rao.)

Africa (toombak). Chewing tobacco is available as flavored loose leaves, plugs or twists and is typically placed in the buccal vestibule for hours while snuff is produced in moist or dry forms.73 Moist snuff is finely cut, flavored tobacco that is individually packaged in pouches while dry snuff is fermented, powdered tobacco that is inhaled or placed in the mouth.74 The manufacturing process (fermentation or pasteurization), composition (tobacco species, nicotine, benzo[a]pyrene, flavoring agents and spices) and concentration of tobaccospecific nitrosamine vary in smokeless tobacco products from different countries and different brands.73 High pH found in Scandinavian snus and Sudanese toombak increases the absorption rate of nicotine.75

sites (FIGURE 8 ).77 STK is usually associated with brown-staining teeth gingival recession, root exposure and attachment loss.77 Advanced lesions of STK present as well-demarcated white plaques of leukoplakia.

Clinical Findings

Smokeless tobacco keratosis (STK) is caused by the habitual use of smokeless tobacco and commonly presents in male adults in the fourth to fifth decade.76,77 However, a recent study from India shows a female predilection for STK, suggesting that the gender predilection is culture specific.78 Early lesions of STK present as poorly demarcated, grayish-white and edematous lesions with wrinkles, parallel ridges and fissures in the area where the tobacco is placed, with buccal and vestibular mucosa as the most commonly involved 230 APRIL

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Malignant Transformation

Approximately 60% of smokelesstobacco users present with mucosal lesions.79 Yet, the relative risk of STK transforming into OSCC ranges from 0.6 to 1.7, with less than 3% of these lesions exhibiting epithelial dysplasia.73,80 The malignant transformation of STK into OSCC is between zero and 1.4%.79,81

Treatment

Early lesions of STK tend to regress upon discontinuation of smokeless tobacco,82 and hence, likely represent a form of contact irritation. Therefore, it is highly recommended that patients be encouraged to discontinue ST use. However, leukoplakia may develop in long-standing lesions of STK, and these should be biopsied for definitive diagnosis.73

Patients From Southeast Asia or India: Oral Submucous Fibrosis

Epidemiologically, there are more than 2.5 million cases of oral submucous fibrosis (OSF) globally, with a marked prominence in Southeast Asian countries and a recent growing incidence in

Western countries due to population migration.83,84 It has been defined as “a debilitating, progressive, irreversible collagen metabolic disorder induced by chronic chewing of areca nut and its commercial preparations. It affects the oral mucosa and occasionally the pharynx and esophagus, leading to mucosal stiffness and functional morbidity and has a substantial risk of malignant transformation.”84,85 OSCC in the background of OSF is one of the most common malignancies in South and Southeast Asian countries because of widespread chewing of areca nut often mixed with tobacco.

Clinical Findings

Adult and elderly populations are more likely to develop OSF, an increased incidence in the pediatric population has been noted more recently.86–88 Most studies show a male predilection with a male to female ratio of 4.9:1.83,87,88 Any oral site can be involved, with the buccal mucosa, retromolar region, soft palate and tonsillar faucial pillars most commonly affected.83 Unlike other OPMDs that are for the most part asymptomatic, this OPMD often is symptomatic presenting with pain, burning and ageusia.83,84 OSF presents as mucosal blanching, tongue depapillation, ulceration and loss of oral pigmentation/pallor with progressive irreversible fibrosis causing restricted mouth opening in advanced stages (FIGURE 9A ). Fibrous “piano wire”-like bands are readily palpable.

Malignant Transformation

Epithelial dysplasia has been reported in 7% to 43% cases of OSF with the malignant transformation rate varying from 1.9% to 9%.84,89 There is a strong dose-response relationship between

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the duration of areca nut chewing and the malignant transformation rate.84 The International Agency for Research on Cancer has classified areca nut as a human carcinogen.90 The exact pathogenesis underlying the malignant transformation is uncertain, but the hypothesis is that coordinated epithelial and mesenchymal interactions result in the development of OSCC. Tissue hypoxia secondary to connective tissue fibrosis promotes angiogenesis, and the epithelial atrophy allows for the accumulation of carcinogenic areca nut components upregulating pro-inflammatory cytokines, and these two processes together increase the likelihood of transformation into OSCC.84,89

Treatment

Management of OSF is often based on clinical staging and includes nonsurgical and surgical approaches.83 Medical management involves the use of different systemic medications (vitamin A, beta carotene, vitamin E, lycopene, curcumin tablets, ferrous ascorbate, folic acid, pentoxifylline), intralesional therapy with steroid and hyaluronidase or interferon-gamma injections as well as physiotherapy exercises to increase mouth opening.83 In severe and advanced stages, surgical excision of fibrous bands with collagen membrane placement is an option. However, to date, no single treatment modality has provided a complete resolution of this condition.83

Palatal Lesions Associated With Reverse Smoking

Reverse smoking is a tobacco habit practiced in some rural areas of India, Southeast Asia and a few communities in South America, where the lit end of a homemade cigar (also known as chutta in India) or cigarette is placed inside the

mouth.91–93 Lesions on the palatal mucosa from reverse smoking are a severe form of nicotinic stomatitis caused by heat such as from pipe smoking. Thermal injury from intense heat, together with combustion products, increases the frequency of palatal lesions in reverse smoking.91

Clinical Findings

Because reverse smoking is socially acceptable for females in Southeast Asia, there is a higher prevalence in adult females after the third decade of

Management of OSF is often based on clinical staging and includes nonsurgical and surgical approaches.

life in comparison to males.92,93 The palatal mucosa and tongue are the two most commonly affected sites.93 The palatal changes include hyperkeratosis, hyperpigmentation, mucosal thickening/ plaques, excrescences, fissuring, nodularity, erythema and ulceration.91–93

Malignant Transformation

Epithelial dysplasia has been reported in 65% of cases and OSCC in 10% of cases, with the remaining cases showing “hyperkeratosis.”94 The prevalence of OSCC from palatal changes of reverse smoking ranges from 1.9% to 18.2% among the endemic population depending on the geographic location.91,93

Treatment

Habit cessation is of paramount importance when palatal changes are

encountered secondary to reverse smoking. Management is stage dependent and includes surgical excision for OSCC.94 The four remaining conditions considered OPMD by the WHO are dyskeratosis congenita, syphilitic glossitis, discoid lupus erythematosus (DLE) and chronic candidiasis. Dyskeratosis congenita is a rare X-linked, autosomal dominant or recessive disorder characterized by nail dystrophy, reticular skin pigmentation and oral leukoplakia, the latter being a known precancerous lesion and has been discussed previously in this paper.95 Syphilitic glossitis is rarely seen today because syphilis is readily treated with antibiotics. Before the introduction of penicillin, salvarsan (a toxic organoarsenic compound) was used to treat syphilis.96 However, long-term use of arsenic may lead to head and neck cancers, including OSCC.97 Therefore, syphilisassociated leukoplakia of the tongue is less likely a direct cause of Treponema pallidum itself but more likely a result of long-term treatment of syphilis with arsenic, which is no longer used today. DLE is a chronic dermatologic autoimmune condition that affects sun-exposed areas of the skin with or without oral involvement.98 Cutaneous DLE is more common than oral DLE and has a malignant transformation rate of 3.4%;99 there are very few reported cases of oral DLE transforming to OSCC,98,100,101 and it may be that malignant transformation occurred because oral DLE Musually treated is an autoimmune disease with immunosuppressive agents, both risk factors for leukoplakia and OSCC. Chronic candidiasis was added as a new OPMD by the WHOSin 2017, but there has been controversy as to whether there is a cause-and-effect relationship rather than an association between Candida and OSCC. Candida is often seen overlying lesions of dysplasia and OSCC, but this by no means proves causation because candidiasis is an opportunistic APRIL 2 0 2 1

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■

10A

10B ■

■

10C

10D

FIGURE S 10 . Candidiasis: white papules and plaques of the maxillary palatal gingiva and hard palatal mucosa (10A ). The resolution of candidiasis after topical antifungal therapy (10B ). Angular cheilitis exhibiting bilateral erythema and macerations involving the lip commissures (10C ). Erythematous candidiasis on the maxillary anterior palatal gingiva and the hard palatal mucosa in contact with maxillary removable partial denture (10D ). (Images 10A and 10B courtesy of Dr. Vidya Sankar.)

infection and areas of dysplasia and OSCC likely exhibit local immunologic perturbation.102,103 Arguments against chronic candidiasis being a precancerous lesion are as follows: 1) It resolves with effective antifungal treatment and does not reflect a true leukoplakia, which is generally irreversible because they harbor genomic mutations (FIGURES 10A and 10B );104 2) Candida infection commonly affects the lip commissures bilaterally (angular cheilitis) (FIGURE 10 C ) as well as the palatal mucosa under dentures, both uncommon areas for OSCC (FIGURE 10D ).105 Biopsies of candidiasis almost always show atypical epithelial cells as a reaction to the candidiasis, and the epithelium reverts to normal once the candidiasis has been treated. It is likely that such reactive features may be misdiagnosed as oral epithelial dysplasia.

Clinical Significance to Dental Providers

General dentists are usually the first clinicians to encounter an OPMD. It is of paramount importance for dental 232 APRIL

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practitioners to be familiar with the specific entities and diagnoses, as early detection can lead to early intervention, and as a result, can prevent the progression to OSCC. It is crucial for dentists to obtain a thorough medical, family and social history at the first visit to evaluate for all risk factors associated with oral cancer, not just smoking and alcohol. Dentists should also assess for common findings suspicious for OSCC such as lymphadenopathy/swelling or facial asymmetry. Likewise, the intraoral examination should include a thorough inspection of the oral cavity, while palpating any sites with mucosal abnormalities and documenting findings with measurements and clinical photographs. These clinical photographs will allow dentists to document the evolution of the lesion over time and should be sent with the biopsy to the pathologists. Here are some simple clinical pearls: ■ Dentists must be aware of OPMD-related risk factors beyond smoking and tobacco.

Every patient should be evaluated at every visit for any OPMDs (TA BLE 3 ), especially the high-risk ones such as leukoplakia and erythroplakia. Any lesion that does not resolve within four to six weeks after removal of sources of trauma or antifungal and/or topical steroid therapy should be biopsied or referred for biopsy (FIGURE 11 ). Hyperkeratosis with dysplasia in leukoplakia does not exclude the risk of future malignant transformation; as such, patients should be monitored closely and small lesions should be completely excised. n

AC KN OW L E DG M E N T S The authors thank Drs. Nathaniel S. Treister, Herve Y. Sroussi, Alessandro Villa, Vidya Sankar, Chandramani B. More and Naman R. Rao for their contributions to the clinical images. RE F E RE N C E S 1. National Cancer Institute. Surveillance, Epidemiology and End Results (SEER) Program — Cancer Stat Facts: Oral Cavity and Pharynx Cancer. seer.cancer.gov/statfacts/html/oralcav. html. Accessed Aug. 18, 2020. 2. Arnaoutakis D, Bishop J, Westra W, Califano JA. Recurrence patterns and management of oral cavity premalignant lesions. Oral Oncol 2013 Aug;49(8):814–7. doi: 10.1016/j. oraloncology.2013.04.008. Epub 2013 May 18. 3. Speight PM, Khurram SA, Kujan O. Oral potentially malignant disorders: Risk of progression to malignancy. Oral Surg Oral Med Oral Pathol Oral Radiol 2018 Jun;125(6):612–627. doi: 10.1016/j.oooo.2017.12.011. Epub 2017 Dec 29. 4. Mello FW, Miguel AFP, Dutra KL, et al. Prevalence of oral potentially malignant disorders: A systematic review and metaanalysis. J Oral Pathol Med 2018 Aug;47(7):633–640. doi: 10.1111/jop.12726. Epub 2018 Jun 6. 5. Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med 2007 Nov;36(10):575–80. doi: 10.1111/j.16000714.2007.00582.x. 6. Napier SS, Speight PM. Natural history of potentially malignant oral lesions and conditions: An overview of the literature. J Oral Pathol Med 2008 Jan;37(1):1–10. doi: 10.1111/j.1600-0714.2007.00579.x. 7. Bouquot JE, Gorlin RJ. Leukoplakia, lichen planus and other oral keratoses in 23,616 white Americans over the age of 35 years. Oral Surg Oral Med Oral Pathol 1986 Apr;61(4):373–81. doi: 10.1016/0030-4220(86)90422-6. 8. Silverman S Jr., Gorsky M. Proliferative verrucous

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TABLE 3

Clinical Features, Malignant Transformation and Management of Common Oral Potentially Malignant Disorders Oral potentially malignant disorders

Clinical presentation

Malignant transformation rate

Treatment

Leukoplakia

Homogenous: • well-delineated (at least in part), uniform white plaque with flat, cracked/fissured surface

3.7%–40.8%

Excision

Nonhomogenous: • verrucous, nodular white plaque or speckled (irregular white and red spots) Proliferative: • persistent, progressive, multifocal white plaques that may appear smooth, fissured, verrucous or erythematous

65%–100%

Erythroplakia

Well-demarcated, flat or slightly elevated/nodular, velvety-red plaque

45%–65%

Excision

Actinic cheilitis

Diffuse, atrophic areas or shallow erosions on the lip with blurring of the lip vermilion-skin interface

1.2%–3.2%

Topical 5-fluorouracil or imiquimod

Oral lichen planus

Well-demarcated white plaques with surrounding erythema and white reticulations

0.4%–1.40%

Topical corticosteroids

Smokeless tobacco keratosis

Early lesions: • poorly demarcated, grayish-white and edematous lesions with wrinkles, parallel ridges and fissures

N/A

Habit cessation

Advanced lesions: • well-demarcated white plaques (leukoplakia)

0–1.4%

Excision

Mucosal blanching, pallor, tongue depapillation, progressive irreversible fibrosis with restricted mouth opening

1.9%–9%

Oral submucous fibrosis

leukoplakia: A follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997 Aug;84(2):154–7. doi: 10.1016/s1079-2104(97)90062-7. 9. Cabay RJ, Morton TH Jr., Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: A review of the literature. J Oral Pathol Med 2007 May;36(5):255–61. doi: 10.1111/j.1600-0714.2007.00506.x. 10. Abadie WM, Partington EJ, Fowler CB, Schmalbach CE. Optimal management of proliferative verrucous leukoplakia: A systematic review of the literature. Otolaryngol Head Neck Surg 2015 Oct;153(4):504–11. doi: 10.1177/0194599815586779. Epub 2015 Jun 4. 11. Villa A, Menon RS, Kerr AR, et al. Proliferative leukoplakia: Proposed new clinical diagnostic criteria. Oral Dis 2018 Jul;24(5):749–760. doi: 10.1111/odi.12830. Epub 2018 May 2. 12. Hansen LS, Olson JA, Silverman S Jr. Proliferative verrucous leukoplakia. A long-term study of 30 patients. Oral Surg Oral Med Oral Pathol 1985 Sep;60(3):285–98. doi: 10.1016/0030-4220(85)90313-5. 13. Natarajan E, Woo SB. Benign alveolar ridge keratosis (oral lichen simplex chronicus): A distinct clinicopathologic entity. J Am Acad Dermatol 2008 Jan;58(1):151–7. doi: 10.1016/j. jaad.2007.07.011. 14. Woo SB, Lin D. Morsicatio mucosae oris — a chronic oral frictional keratosis, not a leukoplakia. J Oral Maxillofac Surg 2009 Jan;67(1):140–6. doi: 10.1016/j.joms.2008.08.040. 15. van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral

Oncol Apr–May 2009;45(4–5):317–23. doi: 10.1016/j. oraloncology.2008.05.016. Epub 2008 Jul 31. 16. Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: A report of 10 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996 Oct;82(4):396– 401. doi: 10.1016/s1079-2104(96)80303-9. 17. Woo SB, Grammer RL, Lerman MA. Keratosis of unknown significance and leukoplakia: A preliminary study. Oral Surg Oral Med Oral Pathol Oral Radiol 2014 Dec;118(6):713– 24. doi: 10.1016/j.oooo.2014.09.016. Epub 2014 Sep 22. 18. Pindborg JJ, Jolst O, Renstrup G, Roed-Petersen B. Studies in oral leukoplakia: A preliminary report on the period prevalence of malignant transformation in leukoplakia based on a follow-up study of 248 patients. J Am Dent Assoc 1968 Apr;76(4):767–71. doi: 10.14219/jada.archive.1968.0127. 19. Yanik EL, Katki HA, Silverberg MJ, et al. Leukoplakia, oral cavity cancer risk and cancer survival in the U.S. elderly. Cancer Prev Res (Phila) 2015 Sep;8(9):857–63. doi: 10.1158/1940-6207.CAPR-15-0091. Epub 2015 Jul 9. 20. Pinto AC, Carames J, Francisco H, et al. Malignant transformation rate of oral leukoplakia-systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol 2020 Jun;129(6):600–611.e2. doi: 10.1016/j.oooo.2020.02.017. Epub 2020 Apr 2. 21. Amagasa T, Yamashiro, M, Ishikawa, H. Oral leukoplakia related to malignant transformation. Oral Sci Int 2006 Nov;3(2):45–55. doi.org/10.1016/S1348-8643(06)80001-7. 22. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Longterm treatment outcome of oral premalignant lesions. Oral Oncol 2006 May;42(5):461–74. doi: 10.1016/j.

• Systemic medications (vitamin A, beta carotene, vitamin E, lycopene, curcumin tablets, ferrous ascorbate, folic acid, pentoxifylline) • Intralesional therapy (steroid and hyaluronidase or interferon-gamma injections) • Surgery oraloncology.2005.08.011. Epub 2005 Nov 28. 23. Schepman KP, van der Meij EH, Smeele LE, van der Waal I. Malignant transformation of oral leukoplakia: A follow-up study of a hospital-based population of 166 patients with oral leukoplakia from The Netherlands. Oral Oncol 1998 Jul;34(4):270–5. 24. Woo SB, Cashman EC, Lerman MA. Human papillomavirus-associated oral intraepithelial neoplasia. Mod Pathol 2013 Oct;26(10):1288–97. doi: 10.1038/ modpathol.2013.70. Epub 2013 Apr 19. 25. Herrero R, Castellsague X, Pawlita M, et al. Human papillomavirus and oral cancer: The International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003 Dec 3;95(23):1772–83. doi: 10.1093/jnci/djg107. 26. Joseph AW, D’Souza G. Epidemiology of human papillomavirus-related head and neck cancer. Otolaryngol Clin North Am 2012 Aug;45(4):739–64. doi: 10.1016/j. otc.2012.04.003. Epub 2012 May 31. 27. Lingen MW, Xiao W, Schmitt A, et al. Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas. Oral Oncol 2013 Jan;49(1):1–8. doi: 10.1016/j.oraloncology.2012.07.002. Epub 2012 Jul 28. 28. Macey R, Walsh T, Brocklehurst P, et al. Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions. Cochrane Database Syst Rev 2015 May 29;2015(5):CD010276. doi: 10.1002/14651858.CD010276.pub2. 29. Warnakulasuriya KA, Johnson NW. Sensitivity and specificity of OraScan (R) toluidine blue mouthrinse in the detection of oral cancer and precancer. J Oral Pathol Med APRIL 2 0 2 1

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Suspicious oral plaque

White plaque (leukoplakia/ erythroleukoplakia)

Localized, poorly demarcated

Remove any source of trauma

Localized, well-demarcated

Follow-up in 2-4 weeks

If completely resolved, likely frictional keratosis or reactive lesion

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Multifocal (proliferative leukoplakia)

Biopsy or refer for biopsy

Dysplasia/OSCC

Persistent white plaque

Excision

No intervention required

Biopsy or refer for biopsy

Hyperkeratosis (reactive)

Hyperkeratosis (not reactive) mild dysplasia

Moderate to severe dysplasia/ OSCC

Follow-up every 6-12 months, rebiopsy if clinical changes occur

Excision or follow-up every 3-6 months, rebiopsy if clinical changes occur

Excision

FIGURE 11. Biopsy flow chart for suspicious oral plaque lesions.

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Red plaque (erythroplakia)

No dysplasia/ OSCC

Treat with topical corticosteroid and rebiopsy any residual lesion. Follow-up every 3 months and biopsy as necessary

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1996 Mar;25(3):97–103. doi: 10.1111/j.1600-0714.1996. tb00201.x. 30. Silverman S Jr., Migliorati C, Barbosa J. Toluidine blue staining in the detection of oral precancerous and malignant lesions. Oral Surg Oral Med Oral Pathol 1984 Apr;57(4):379–82. doi.org/10.1016/00304220(84)90154-3. 31. Farah CS, McIntosh L, Georgiou A, McCullough MJ. Efficacy of tissue autofluorescence imaging (VELScope) in the visualization of oral mucosal lesions. Head Neck 2012 Jun;34(6):856–62. doi: 10.1002/hed.21834. Epub 2011 Aug 4. 32. Asge Technology Committee, Song LM, Adler DG, et al. Narrow band imaging and multiband imaging. Gastrointest Endosc 2008 Apr;67(4):581–9. doi: 10.1016/j. gie.2008.01.013. 33. Bhatia N, Lalla Y, Vu AN, Farah CS. Advances in optical adjunctive AIDS for visualisation and detection of oral malignant and potentially malignant lesions. Int J Dent 2013;2013:194029. doi: 10.1155/2013/194029. Epub 2013 Sep 2. 34. Chu PY, Tsai TL, Tai SK, Chang SY. Effectiveness of narrow band imaging in patients with oral squamous cell carcinoma after treatment. Head Neck 2012 Feb;34(2):155–61. doi: 10.1002/hed.21704. Epub 2011 Feb 14. 35. Lodi G, Porter S. Management of potentially malignant disorders: Evidence and critique. J Oral Pathol Med 2008 Feb;37(2):63–9. doi: 10.1111/j.1600-0714.2007.00575.x. 36. Kramer IR, Lucas RB, Pindborg JJ, Sobin LH. Definition of leukoplakia and related lesions: An aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 1978 Oct;46(4):518–39. 37. Shafer WG, Waldron CA. Erythroplakia of the oral cavity. Cancer 1975 Sep;36(3):1021–8. doi: 10.1002/1097-0142(197509)36:3<1021::aidcncr2820360327>3.0.co;2-w. 38. Hashibe M, Jacob BJ, Thomas G, et al. Socioeconomic status, lifestyle factors and oral premalignant lesions. Oral Oncol 2003 Oct;39(7):664–71. doi: 10.1016/s13688375(03)00074-5. 39. Reichart PA, Philipsen HP. Oral erythroplakia — a review. Oral Oncol 2005 Jul;41(6):551–61. doi: 10.1016/j. oraloncology.2004.12.003. Epub 2005 Apr 9. 40. Villa A, Villa C, Abati S. Oral cancer and oral erythroplakia: An update and implication for clinicians. Aust Dent J 2011 Sep;56(3):253–6. doi: 10.1111/j.18347819.2011.01337.x. Epub 2011 Jul 10. 41. Lapthanasupkul P, Poomsawat S, Punyasingh J. A clinicopathologic study of oral leukoplakia and erythroplakia in a Thai population. Quintessence Int 2007 Sep;38(8):e448–55. 42. Yang SW, Lee YS, Chang LC, Hsieh TY, Chen TA. Outcome of excision of oral erythroplakia. Br J Oral Maxillofac Surg 2015 Feb;53(2):142–7. doi: 10.1016/j.bjoms.2014.10.016. Epub 2014 Nov 18. 43. Yaldiz M. Prevalence of actinic keratosis in patients attending the dermatology outpatient clinic. Medicine (Baltimore) 2019 Jul;98(28):e16465. doi: 10.1097/ MD.0000000000016465. 44. Markopoulos A, Albanidou-Farmaki E, Kayavis I. Actinic cheilitis: Clinical and pathologic characteristics in 65 cases. Oral Dis 2004 Jul;10(4):212–6. doi: 10.1111/j.16010825.2004.01004.x.

45. Kaugars GE, Pillion T, Svirsky JA, et al. Actinic cheilitis: A review of 152 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999 Aug;88(2):181–6. doi: 10.1016/s10792104(99)70115-0. 46. Lopes ML, Silva Junior FL, Lima KC, Oliveira PT, Silveira EJ. Clinicopathological profile and management of 161 cases of actinic cheilitis. An Bras Dermatol Jul–Aug 2015;90(4):505– 12. doi: 10.1590/abd1806-4841.20153848. 47. Pinera-Marques K, Lorenco SV, Silva LF, Sotto MN, Carneiro PC. Actinic lesions in fishermen’s lower lip: Clinical, cytopathological and histopathologic analysis. Clinics (Sao Paulo) 2010 Apr;65(4):363–7. doi: 10.1590/S180759322010000400003. 48. Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: A comparison of clinical and histological outcomes including one-year follow-up. Br J Dermatol 2007 Dec;157 Suppl 2:34–40. doi: 10.1111/j.13652133.2007.08271.x. 49. Jansen MHE, Kessels J, Nelemans PJ, et al. Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med 2019;380(10):935–46. doi: 10.1056/ NEJMoa1811850. 50. Tosti A, Peluso AM, Fanti PA, Piraccini BM. Nail lichen planus: Clinical and pathologic study of 24 patients. J Am Acad Dermatol 1993 May;28(5 Pt 1):724–30. doi: 10.1016/0190-9622(93)70100-8. 51. Mignogna MD, Lo Russo L, Fedele S. Gingival involvement of oral lichen planus in a series of 700 patients. J Clin Periodontol 2005 Oct;32(10):1029–33. doi: 10.1111/j.1600-051X.2004.00761.x. 52. Eisen D. The evaluation of cutaneous, genital, scalp, nail, esophageal and ocular involvement in patients with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999 Oct;88(4):431–6. doi: 10.1016/s10792104(99)70057-0. 53. Li C, Tang X, Zheng X, et al. Global prevalence and incidence estimates of oral lichen planus: A systematic review and meta-analysis. JAMA Dermatol 2020 Feb 1;156(2):172– 181. doi: 10.1001/jamadermatol.2019.3797. 54. Carrozzo M. Oral diseases associated with hepatitis C virus infection. Part 2: Lichen planus and other diseases. Oral Dis 2008 Apr;14(3):217–28. doi: 10.1111/j.16010825.2007.01432.x. Epub 2008 Jan 22. 55. Zhou XJ, Sugerman PB, Savage NW, Walsh LJ, Seymour GJ. Intra-epithelial CD8+ T cells and basement membrane disruption in oral lichen planus. J Oral Pathol Med 2002 Jan;31(1):23–7. doi: 10.1046/j.0904-2512.2001.10063.x. 56. Yuan A, Woo SB. Adverse drug events in the oral cavity. Oral Surg Oral Med Oral Pathol Oral Radiol 2015 Jan;119(1):35–47. doi: 10.1016/j.oooo.2014.09.009. Epub 2014 Sep 17. 57. Thornhill MH, Sankar V, Xu XJ, et al. The role of histopathological characteristics in distinguishing amalgamassociated oral lichenoid reactions and oral lichen planus. J Oral Pathol Med 2006 Apr;35(4):233–40. doi: 10.1111/j.1600-0714.2006.00406.x. 58. Li D, Li J, Li C, Chen Q, Hua H. The Association of Thyroid Disease and Oral Lichen Planus: A literature review and metaanalysis. Front Endocrinol (Lausanne) 2017 Nov 9;8:310. doi: 10.3389/fendo.2017.00310. eCollection 2017. 59. Setterfield JF, Neill S, Shirlaw PJ, et al. The vulvovaginal

gingival syndrome: A severe subgroup of lichen planus with characteristic clinical features and a novel association with the class II HLA DQB1*0201 allele. J Am Acad Dermatol 2006 Jul;55(1):98–113. doi: 10.1016/j.jaad.2005.12.006. 60. Petruzzi M, De Benedittis M, Pastore L, Grassi FR, Serpico R. Peno-gingival lichen planus. J Periodontol 2005 Dec;76(12):2293–8. doi: 10.1902/jop.2005.76.12.2293. 61. Holmstrup P, Pindborg JJ. Erythroplakic lesions in relation to oral lichen planus. Acta Derm Venereol Suppl (Stockh) 1979;59(85):77–84. 62. Markopoulos AK, Antoniades D, Papanayotou P, Trigonidis G. Malignant potential of oral lichen planus; a follow-up study of 326 patients. Oral Oncol 1997 Jul;33(4):263–9. doi: 10.1016/s0964-1955(97)00005-5. 63. Carbone M, Conrotto D, Carrozzo M, et al. Topical corticosteroids in association with miconazole and chlorhexidine in the long-term management of atrophic-erosive oral lichen planus: A placebo-controlled and comparative study between clobetasol and fluocinonide. Oral Dis 1999 Jan;5(1):44–9. doi: 10.1111/j.1601-0825.1999.tb00063.x. 64. Jacob SE, Steele T. Corticosteroid classes: A quick reference guide including patch test substances and crossreactivity. J Am Acad Dermatol 2006 Apr;54(4):723–7. doi: 10.1016/j.jaad.2005.12.028. 65. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician 2009 Jan;79(2):135–40. 66. Alsarraf A, Mehta K, Khzam N. The gingival oral lichen planus: A periodontal-oral medicine approach. Case Rep Dent 2019 Jan 6;2019:4659134. doi: 10.1155/2019/4659134. eCollection 2019. 67. Alrashdan MS, Cirillo N, McCullough M. Oral lichen planus: A literature review and update. Arch Dermatol Res 2016 Oct;308(8):539–51. doi: 10.1007/s00403-0161667-2. Epub 2016 Jun 27. 68. Lajevardi V, Ghodsi SZ, Hallaji Z, et al. Treatment of erosive oral lichen planus with methotrexate. J Dtsch Dermatol Ges 2016 Mar;14(3):286–93. doi: 10.1111/ddg.12636. 69. Yeshurun A, Bergman R, Bathish N, Khamaysi Z. Hydroxychloroquine sulphate therapy of erosive oral lichen planus. Australas J Dermatol 2019 May;60(2):e109–e112. doi: 10.1111/ajd.12948. Epub 2018 Nov 8. 70. Wang TW, Asman K, Gentzke AS, et al. Tobacco product use among adults — United States, 2017. MMWR Morb Mortal Wkly Rep 2018;67(44):1225–32. 71. Kulik MC, Glantz SA. The smoking population in the USA and EU is softening not hardening. Tob Control 2016 Jul;25(4):470–5. doi: 10.1136/ tobaccocontrol-2015-052329. Epub 2015 Jun 24. 72. Hallikeri K, Naikmasur V, Guttal K, Shodan M, Chennappa NK. Prevalence of oral mucosal lesions among smokeless tobacco usage: A cross-sectional study. Indian J Cancer Oct– Dec 2018;55(4):404–409. doi: 10.4103/ijc.IJC_178_18. 73. Rodu B, Jansson C. Smokeless tobacco and oral cancer: A review of the risks and determinants. Crit Rev Oral Biol Med 2004 Sep 1;15(5):252–63. doi: 10.1177/154411130401500502. 74. Andersson G, Axell T, Larsson A. Histologic changes associated with the use of loose and portion-bag packed Swedish moist snuff: A comparative study. J Oral Pathol Med 1989 Oct;18(9):491–7. doi: 10.1111/j.1600-0714.1989. tb01349.x. 75. Idris AM, Ibrahim SO, Vasstrand EN, et al. The Swedish snus and the Sudanese toombak: Are they different? Oral APRIL 2 0 2 1

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Oncol 1998 Nov;34(6):558–66. doi: 10.1016/s13688375(98)00047-5. 76. Mehta FS, Shroff BC, Gupta PC, Daftary DK. Oral leukoplakia in relation to tobacco habits. A 10-year followup study of Bombay policemen. Oral Surg Oral Med Oral Pathol 1972 Sep;34(3):426–33. doi: 10.1016/00304220(72)90319-2. 77. Greer RO Jr. Oral manifestations of smokeless tobacco use. Otolaryngol Clin North Am 2011 Feb;44(1):31–56, v. doi: 10.1016/j.otc.2010.09.002. 78. Samatha Y, Sankar AJ, Ganapathy KS, et al. Clinicopathologic evaluation of lesions associated with tobacco usage. J Contemp Dent Pract 2014 Jul 1;15(4):466–72. doi: 10.5005/jp-journals-10024-1564. 79. Vigneswaran N, Tilashalski K, Rodu B, Cole P. Tobacco use and cancer. A reappraisal. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995 Aug;80(2):178–82. doi: 10.1016/ s1079-2104(05)80199-4. 80. Rodu B, Cole P. Smokeless tobacco use and cancer of the upper respiratory tract. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002 May;93(5):511–5. doi: 10.1067/ moe.2002.123497. 81. Rodu B, Plurphanswat N. Mortality among male smokers and smokeless tobacco users in the USA. Harm Reduct J 2019 Aug 20;16(1):50. doi: 10.1186/s12954-019-0321-7. 82. Giunta JL, Connolly G. The reversibility of leukoplakia caused by smokeless tobacco. J Am Dent Assoc 1986 Jul;113(1):50–2. doi: 10.14219/jada.archive.1986.0128. 83. More CB, Gavli N, Chen Y, Rao NR. A novel clinical protocol for therapeutic intervention in oral submucous fibrosis: An evidence based approach. J Oral Maxillofac Pathol Sep–Dec 2018;22(3):382–391. doi: 10.4103/jomfp.JOMFP_223_18. 84. Rao NR, Villa A, More CB, et al. Oral submucous fibrosis: A contemporary narrative review with a proposed interprofessional approach for an early diagnosis and clinical management. J Otolaryngol Head Neck Surg 2020 Jan 8;49(1):3. doi: 10.1186/s40463-020-0399-7. 85. More CB, Rao NR. Proposed clinical definition for oral submucous fibrosis. J Oral Biol Craniofac Res Oct–Dec 2019;9(4):311–314. doi: 10.1016/j.jobcr.2019.06.016. Epub 2019 Jul 2. 86. More CB, Rao NR, Hegde R, et al. Oral submucous fibrosis in children and adolescents: Analysis of 36 cases. J Indian Soc Pedod Prev Dent Apr–Jun 2020;38(2):190–199. doi: 10.4103/JISPPD.JISPPD_173_20. 87. Gupta PC, Bhonsle RB, Murti PR, et al. An epidemiologic assessment of cancer risk in oral precancerous lesions in India with special reference to nodular leukoplakia. Cancer 1989 Jun 1;63(11):2247–52. doi: 10.1002/1097-0142(19890601)63:11<2247::aidcncr2820631132>3.0.co;2-d. 88. More CB, Rao NR, More S, Johnson NW. Reasons for initiation of areca nut and related products in patients with oral submucous fibrosis within an endemic area in Gujarat, India. Subst Use Misuse 2020;55(9):1413–1421. doi: 10.1080/10826084.2019.1660678. 89. Ray JG, Ranganathan K, Chattopadhyay A. Malignant transformation of oral submucous fibrosis: Overview of histopathological aspects. Oral Surg Oral Med Oral Pathol Oral Radiol 2016 Aug;122(2):200–9. doi: 10.1016/j. oooo.2015.11.024. Epub 2016 Apr 19. 90. Humans IWGotEoCRt. Betel-quid and areca-nut chewing and some areca-nut derived nitrosamines. IARC Monogr Eval

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Carcinog Risks Hum 2004;85:1-334. 91. Alvarez Gomez GJ, Alvarez Martinez E, Jimenez Gomez R, et al. Reverse smokers and changes in oral mucosa. Department of Sucre, Colombia. Med Oral Patol Oral Cir Bucal 2008 Jan;13(1):E1–8. 92. Ortiz GM, Pierce AM, Wilson DF. Palatal changes associated with reverse smoking in Filipino women. Oral Dis 1996 Sep;2(3):232–7. doi: 10.1111/j.1601-0825.1996.tb00230.x. 93. Pindborg JJ, Mehta FS, Gupta PC, Daftary DK, Smith CJ. Reverse smoking in Andhra Pradesh, India: A study of palatal lesions among 10,169 villagers. Br J Cancer 1971 Mar;25(1):10–20. doi: 10.1038/bjc.1971.2. 94. Dharmavaram AT, Nallakunta R, Reddy SR, Chennoju SK. Demystifying the enigma of smoking — an observational comparative study on tobacco smoking. J Clin Diagn Res 2016 Apr;10(4):ZC94–9. doi: 10.7860/JCDR/2016/16359.7677. Epub 2016 Apr 1. 95. Mason PJ, Bessler M. The genetics of dyskeratosis congenita. Cancer Genet 2011 Dec;204(12):635–45. doi: 10.1016/j. cancergen.2011.11.002. 96. Gelpi A, Tucker JD. The magic bullet hits many targets: Salvarsan’s impact on UK health systems, 1909–1943. Sex Transm Infect 2015 Feb;91(1):69–70. doi: 10.1136/ sextrans-2014-051780. 97. Khlifi R, Olmedo P, Gil F, et al. Arsenic, cadmium, chromium and nickel in cancerous and healthy tissues from patients with head and neck cancer. Sci Total Environ 2013 May 1;452–453:58–67. doi: 10.1016/j.scitotenv.2013.02.050. Epub 2013 Mar 15. 98. Ranginwala AM, Chalishazar MM, Panja P, Buddhdev KP, Kale HM. Oral discoid lupus erythematosus: A study of 21 cases. J Oral Maxillofac Pathol 2012 Sep;16(3):368–73. doi: 10.4103/0973-029X.102487. 99. Fernandes MS, Girisha BS, Viswanathan N, Sripathi H, Noronha TM. Discoid lupus erythematosus with squamous cell carcinoma: A case report and review of the literature in Indian patients. Lupus 2015 Dec;24(14):1562–6. doi: 10.1177/0961203315599245. Epub 2015 Aug 6. 100. Schiodt M. Oral discoid lupus erythematosus. III. A histopathologic study of 66 patients. Oral Surg Oral Med Oral Pathol 1984 Mar;57(3):281–93. doi: 10.1016/00304220(84)90184-1. 101. Savage NW, Boras VV, Zaini ZM. Oral squamous cell carcinoma with discoid lupus erythematosus. Oral Oncology Extra 2006;42(1):32–35. doi.org/10.1016/j. ooe.2005.08.006. 102. McCullough M, Jaber M, Barrett AW, et al. Oral yeast carriage correlates with presence of oral epithelial dysplasia. Oral Oncol 2002 Jun;38(4):391–3. doi: 10.1016/s13688375(01)00079-3. 103. Barrett AW, Kingsmill VJ, Speight PM. The frequency of fungal infection in biopsies of oral mucosal lesions. Oral Dis 1998 Mar;4(1):26–31. doi: 10.1111/j.1601-0825.1998. tb00251.x. 104. Villa A, Hanna GJ, Kacew A, et al. Oral keratosis of unknown significance shares genomic overlap with oral dysplasia. Oral Dis 2019 Oct;25(7):1707–1714. doi: 10.1111/odi.13155. Epub 2019 Jul 23. 105. Sitheeque MA, Samaranayake LP. Chronic hyperplastic candidosis/candidiasis (candidal leukoplakia). Crit Rev Oral Biol Med 2003;14(4):253–67. doi: 10.1177/154411130301400403.

T HE CORRE S P ON DIN G AU T HOR , Diana Wang, DDS, can be reached at Diana_Wang@hsdm.harvard.edu.

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treatment complications C D A J O U R N A L , V O L 4 9 , Nº 4

Oral Complications From the Treatment of Oral Cavity and Oropharyngeal Cancers Karen He, BA; Trevor G. Hackman, MD; Siddharth Sheth, DO; Bhishamjit S. Chera, MD; and Muhammad A. Shazib, DMD

abstract Background: Patients with oral cavity and oropharyngeal cancer (OC/OP) often develop treatmentassociated complications in the oral cavity. Dentists play a significant role in recognizing and managing treatment-associated oral complications of OC/OP. Methods: Utilizing a combination of the latest published literature, clinical guidelines and textbooks, we summarized the short- and long-term oral complications that can arise in patients undergoing treatment for oral cavity/oropharyngeal cancers and provide dental treatment guidelines for oral health practitioners. Results: Treatment-associated side effects for OC/OP cancers include both acute and chronic toxicities. Short-term complications include oral mucositis, infections, bleeding, immune-related adverse events and taste disturbances. Long-term complications include osteoradionecrosis, salivary gland dysfunction, dental caries, trismus, neuropathic pain and secondary cancers. Conclusions: Continued improvements in treatment methods for OC/OP cancers have increased the average life expectancy after diagnosis. However, the sequelae of oral complications following treatment for OC/OP cancers is complex and often has a significant impact on patients’ quality of life. Practical implications: Dental providers have an important role in the evaluation and management of patients’ oral health before, during and following treatment for OC/OP cancers. Key words: Head and neck cancer, oral cavity cancer, oropharyngeal cancer, oral toxicities, dental oncology, xerostomia, osteoradionecrosis, oral irAE, mucositis, oral oncology

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AUTHORS Karen He, BA, is a predoctoral dental student (DMD) at the Harvard School of Dental Medicine in Boston. Conflict of Interest Disclosure: None reported. Trevor G. Hackman, MD, is a professor and vice chair, inpatient operations and quality, and the director of the head and neck fellowship, department of otolaryngology/head and neck surgery at the University of North Carolina School of Medicine in Chapel Hill, N.C. Conflict of Interest Disclosure: None reported. Siddharth Sheth, DO, is an assistant professor in the department of medical oncology at the University of North Carolina School of Medicine in Chapel Hill, N.C. Conflict of Interest Disclosure: None reported.

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Bhishamjit S. Chera, MD, is an associate professor and the associate chair of clinical operations and improvement and the director of patient safety and quality, department of radiation oncology at the University of North Carolina School of Medicine in Chapel Hill, N.C. Conflict of Interest Disclosure: Dr. Chera holds ownership interest (including patents) in and is a consultant/advisory board member for Naveris Inc. Muhammad Ali Shazib, DMD, is an assistant professor and medical director of UNC Hospitals Oral Medicine Services, division of craniofacial and surgical care at the University of North Carolina, Adams School of Dentistry, Chapel Hill, N.C. Conflict of Interest Disclosure: None reported.

n 2020, an estimated 53,260 Americans were diagnosed with oral cavity and oropharyngeal (OC/ OP) cancer, accounting for 3% of all cancers diagnosed in the United States each year.1 OC/OP cancers are a heterogeneous category of malignancies that includes squamous cell carcinoma (SCC), minor salivary gland carcinoma, lymphoma and melanoma. Anatomically, OC/OP cancers include cancers of the oral cavity, which are the lips, gingiva, hard palate, tongue and floor of the mouth, and cancers of the oropharynx, which are the base of tongue, tonsils and the soft and hard palate. Traditionally, the risk factors for developing OC/ OP cancers included tobacco use and heavy alcohol consumption. However, as public awareness about the link between tobacco and cancer became known and rates of tobacco consumption decreased starting in the early 1970s, the incidence of tobacco-related OC/OP cancers has steadily decreased since then. In contrast, the incidence of oropharyngeal cancers specifically linked to sexually transmitted human papillomavirus (HPV) infection has been on the rise, with HPV-positive tumors estimated to account for 70% of all oropharyngeal cancers today.2 Between 2007 and 2016, while the overall incidence of OC/OP cancers increased 0.6% per year on average, this appears largely due to the increase in HPV-associated cancers by 2.1% per year, which is not offset by the 0.4% decrease by non-HPV-associated cancers.3 The mortality rate of OC/OP cancers has decreased in the last 30 years due to continued improvements in treatment methods and favorable outcomes of HPVassociated oropharyngeal cancers, leading to an increasing population of survivors who are left to deal with post-treatment complications. Treatment-associated side effects for oral cancer range from acute

toxicities such as oral mucositis and acute infections to more chronic toxicities such as osteoradionecrosis, salivary gland dysfunction, trismus, microbiome shifts and secondary cancers. These side effects, which are largely thought to be secondary to the radiation damage to microvascular circulation, have detrimental effects on the quality of life for survivors including xerostomia, taste disturbances, difficulty with speech and mastication, dental caries and feeding-tube dependence. As this population of cancer survivors continues to increase, it is imperative for dentists to be aware of the short- and long-term oral complications that can arise in patients undergoing treatment for OC/OP cancers, familiarize themselves with management options for these complications and remain vigilant in screening for any recurrent neoplasms. The article provides guidelines to general dentists on how to complete a comprehensive evaluation before and during the course of treatment and to recognize complications of treatment with which patients with diagnosed OC/OP cancers may present.

Current Treatment Approach

Over 90% of OC/OP cancers are squamous cell carcinoma.4 Treatment for these cancers depends on multiple factors, including location and stage of the cancer. Due to the favorable treatment response of HPV-positive oropharyngeal cancers in particular, the American Joint Committee on Cancer (AJCC) 8th edition staging criteria for OC/OP cancers is stratified by HPV-status, with high-risk HPV positive OC/OP cancers16,18,31,33 staged less aggressively than HPV negative OC/ OP cancers.5,6 According to the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of OC/OP cancers, early-stage disease (local

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tumor without locoregional involvement or distant spread) is typically treated with either surgery or radiation therapy alone. Advanced disease (tumor with locoregional involvement and distant spread) usually involves either surgery and postoperative adjuvant radiation therapy with or without chemotherapy (standard of care for the oral cavity and other subsites) or concurrent chemoradiation therapy (a primary treatment option for non-oral cavity upper aerodigestive tract SCC).7 For unresectable oral cavity cancers, definitive radiotherapy is usually the primary treatment modality. Recurrent or metastatic cancers are now treated with chemotherapy, immune checkpoint inhibitors (ICI) such as programmed cell death 1 receptor (PD-1) or a combination of chemotherapy and ICI.8

Treatment Modalities

Surgical resection is commonly used as the definitive treatment in earlystage cancers, particularly in the oral cavity. Primary tumor resection may either be localized and involve primarily closure or it may involve a broad surface area or multiple sites and may require reconstruction with skin, graft, local flap, regional flap reconstruction or microvascular free tissue transfers. Neck dissection is typically performed in patients with advanced-stage cancer who have nodal disease or large primary tumors with increased risk for lymph node metastasis. Complications from surgical resection include facial disfigurement and/or functional impairment of speech and mastication. Radiation therapy uses high-energy X-rays or particles to destroy cancer cells or slow their rate of growth. Radiation dose is determined by location, type and extent of the spread of disease. Most patients receiving definitive

adjuvant radiotherapy will receive a total dose of 70 Gy administered in 2 Gy fractions five times a week over the course of seven weeks.9,10 The type and severity of complications is related to the total dose of radiation given. Complications of radiation therapy include radiation-related oral mucositis, hyposalivation, xerostomia, neuropathic pain, taste disturbance, radiation caries, osteoradionecrosis and trismus. Chemotherapy is given systemically and typically administered intravenously. These cytotoxic agents destroy rapidly dividing cells during specific stages of the cell replication cycle. Common chemotherapeutic drugs used to treat OC/OP cancers include cisplatin, carboplatin, cetuximab, 5-fluorouracil (5-FU), paclitaxel (Taxol) and docetaxel (Taxotere). Oral complications resulting from chemotherapy include fatigue, bleeding, nausea, altered saliva, taste changes and mucositis. Infections may also occur including Candida albicans and herpesvirus, which are most common. The chemotherapy regimen for OC/OP cancers is usually given concomitantly with radiation therapy (adjuvant) and is typically less aggressive than regimens for patients undergoing myeloablative conditioning in preparation for allogeneic stem cell transplant for hematologic malignancies. Immunotherapy is now FDA approved for recurrent or metastatic OC/ OP cancers. These therapies enhance the host’s immune system to identify and kill cancer cells. Immunotherapies include ICIs such as PD-1 inhibitors and CTLA4 (cytotoxic T-lymphocyte associated protein 4) inhibitors. Pembrolizumab (Keytruda) and nivolumab (Opdivo) are ICIs that target PD-1, a receptor on T cells’ surface that when activated helps cancer cells evade detection by the immune system. Inhibition

AJCC

American Joint Committee on Cancer

Allo-HCT

Allogeneic hematopoietic stem cell transplant

ANC

Absolute neutrophil count

CIT

Chemotherapy-induced thrombocytopenia

CTLA-4

Cytotoxic T-lymphocyte associated protein 4

ICI

Immune checkpoint inhibitors

IMRT

Intensity-modulated radiotherapy

irAE

Immune-related adverse events

MASCC/ ISOO

Multinational Association of Supportive Care in Cancer/ International Society for Oral Oncology

NCCN

National Comprehensive Cancer Network

NCI

The National Cancer Institute

OC/OP

Oral cavity and oropharyngeal

ORN

Osteoradionecrosis

PD-1

Programmed cell death 1 receptor

TPO

Thrombopoietin

of PD-1 results in T cell activation and shrinkage of tumor size. Due to upregulation of the host immune system, ICIs may induce oral immunerelated adverse events (irAE) such as lichenoid reaction, erythema multiforme and vesiculobullous disorders.11,12

Complications of Treatment Radiation Therapy

Oral Mucositis Radiotherapy-induced oral mucositis is a severe, common toxicity of radiation that presents as painful ulceration and erythema of oral mucosa (FIGURE 1A ). Acute mucositis affects over 80% of patients undergoing radiotherapy. Risk factors include poor oral hygiene, compromised liver and kidney function and total dose and fraction size of ionizing radiation received.13 Symptoms of acute mucositis develop upon receiving threshold doses of radiation. At 10 Gy, patients may develop erythema, a burning sensation and intolerance to spicy foods. At 30 Gy, mucosal APRIL 2 0 2 1

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ulcerations and major salivary gland damage develop with associated increased pain and difficulty consuming a normal diet. While the disease course is typically limited to the duration of radiation therapy, symptoms of oral mucositis may persist for up to eight weeks after completion of treatment.14 A small group of patients (8%) may have persistent oral mucositis more than three months after completion of radiotherapy, which is known as chronic mucositis.15,16 Chemotherapy-induced oral mucositis has an earlier onset and shorter clinical course than radiationinduced mucositis.14 Mucosal ulceration is seen seven to 10 days following the administration of chemotherapeutic agents and spontaneous healing occurs by three weeks.17,18 For patients undergoing concurrent chemotherapy with radiation therapy, the onset of mucositis may be earlier, duration may be longer and symptoms more severe.19 The severity of mucositis can be quantified by standardized systems developed by both the World Health Organization (WHO) and The National Cancer Institute (NCI). The WHO system is graded on a scale of 0 to 4 based on a combination of subjective (pain), objective (presence of erythema and/or ulceration) and functional (ability to eat) criteria. The NCI system reports a separate clinical/objective score and functional/ symptomatic score between 0 and 4. For patients, mucositis is often one of the most debilitating and painful complications of cancer treatment that can be severe enough to interrupt treatment regimens and increase length of hospital stay. The incremental cost of treating oral mucositis due to radiotherapy ranges from $5,000 to $30,00020,21 per affected patient. The heavy burden of 242 APRIL

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mucositis on both patient well-being and the health care system makes the disease an important research target. The pathogenesis of oral mucositis is multifactorial, and a key mechanism is the direct cytotoxic effect of radiation and chemotherapy leading to apoptosis of oral epithelial cells at a cellular level and mucosal ulceration at a clinical level. Many pathways have been proposed to explain the biological basis for cell death, including the five-stage model proposed by Sonis et al. involving pro-inflammatory cytokines and mediators.22 In addition

Chemotherapy-induced oral mucositis has an earlier onset and shorter clinical course than radiation-induced mucositis.

to the tissue injury model of mucositis, there may be a relationship between variations in oral microbiome and development of mucositis, however a clear link has not been established to date.23 Management for mucositis is mainly palliative. Currently, intravenous recombinant human keratinocyte growth factor-1, palifermin (Kepivance), is the only FDA-approved drug to treat oral mucositis in patients with hematologic cancers.24 However, palifermin has not been used widely for mucositis in head and neck cancer patients due to the high cost of therapy.25 A second promising drug currently in phase III clinical trials is avasopasem manganese (Galera Therapeutics, Malvern, Penn.), a radioprotective agent whose clinical use has been limited due to the difficulty of its daily

intravenous method of administration.25 Photobiomodulation therapy, previously known as low-level laser therapy, is recommended for the prevention of radiation- and chemotherapy-induced oral mucositis. Oral cryotherapy, or use of ice chips, has also proven effective in the prevention of chemotherapy-induced (specifically 5-fluorouracil) oral mucositis. Dental considerations from the authors and 2019 guidelines set by the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) for management of oral mucositis include the following: ■ Patients should visit their dentist before, during and after treatment to ensure dental needs are taken care of promptly. Dentists should educate their patients on the importance of maintaining excellent oral hygiene during treatment to prevent the development of local or systemic infections, including brushing with a soft toothbrush and fluoridated toothpaste, flossing and use of nonmedicated mouthwashes (saline or sodium bicarbonate rinse) to promote oral clearance. ■ Recommendation of the following agents for symptomatic relief: • Analgesic mouthwash such as lidocaine 2% oral solution. • Mucoadhesive agents such as Gelclair. • Topical tricyclic antidepressant such as doxepin hydrochloride solution. • Supersaturated calcium phosphate solution such as Caphosol solution. Hyposalivation Hyposalivation and xerostomia caused by radiation therapy can lead to

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pain, stomatitis, infection, development of dental caries or periodontal disease and difficulties in swallowing and mastication. Hyposalivation is caused by irradiation of the salivary glands resulting in damage to salivary acinar cells (FIGURE 1B ). Major salivary glands are often affected by radiation if the location of the primary tumor is nearby and the field of radiation encompasses both structures. Cumulative doses of radiation surpassing 50 Gy can lead to irreversible salivary gland damage and permanently reduced salivary function. In patients whose major salivary glands (parotid, submandibular, sublingual glands) were within the treated fields of radiotherapy, the prevalence of xerostomia is almost ubiquitous with conventional radiation therapy. To limit the exposure of normal tissue to radiation, intensity-modulated radiotherapy (IMRT), which focuses a higher dose of radiation on tumor tissue, was developed. Introduction of IMRT has been reported to successfully reduce the incidence of xerostomia to less than 30% in head and neck cancer patients.26 Management of hyposalivation includes the use of saliva substitutes, topical saliva stimulants and systemic sialogogues. In cases where patients have residual salivary gland function, the use of pharmacologic sialogogues such as cholinomimetics may increase salivary secretion. Currently, pilocarpine (Salagen) and cevimeline (Evoxac) are considered first-line therapy in head and neck cancer patients with radiotherapy-induced hyposalivation and severe xerostomia. Side effects are caused by the generalized effect of parasympathomimetic stimulation including nausea, sweating, urinary frequency, diarrhea and blurred vision (less frequently). Patients who have a history of glaucoma, chronic obstructive pulmonary disease (COPD), peptic

FIGURE S 1. Common oral complications associated with OC/OP cancers. Oral mucositis secondary to chemoradiation therapy (1A ). Salivary gland hypofunction secondary to radiation therapy (1B ). Osteonecrosis of the jaw secondary to radiation therapy (1C ). Oral immune-related adverse event: Oral ulceration with erythema secondary to pembrolizumab (PD-1 inhibitor) for a patient with metastatic SCC of the oral cavity (1D ).

ulcer disease, arrhythmias and coronary vascular disease should avoid the use of cholinomimetics, particularly pilocarpine.27 Amifostine (Ethyol), a freeradical scavenger that protects oral tissues from radiation damage to cell DNA, has also been shown to reduce the incidence of xerostomia when administered prior to radiotherapy.28,29 However, the onerous side effects make amifostine clinically underutilized.30 In patients with limited/no salivary gland function, salivary stimulants and pharmacologic sialagogues may not be effective. In this case, saliva substitutes are recommended. Dental considerations: ■ Encourage patients to hydrate more often to help alleviate symptoms of xerostomia. Drink 40 ounces of water per day and minimize caffeine intake. ■ Counsel patients to avoid smoking and alcohol consumption. ■ Agents for symptomatic relief: • Salivary stimulants such as sugarless lozenges or chewing gum.

• Saliva substitutes such as ACT, Biotène, Mouth Kote, Oasis Moisturizing Mouth Spray, XyliMelts, Xerostom or other formulations containing carboxymethylcellulose. ■ Use of pharmacologic sialagogues such as pilocarpine may help patients with residual salivary gland function to increase saliva production. Taste Disturbances Taste alterations can result from direct radiation damage to cells in the taste buds. However, these changes are typically transient and complete recovery is expected within one year of treatment. Zinc sulfate and hydration have been reported to help with recovery of taste disturbance.31 Radiation Caries Radiation caries are a devastating consequence of radiotherapy. Unlike caries in the nonirradiated population, radiation caries typically APRIL 2 0 2 1

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present on the cervical one-third of the labial surface of teeth. Radiation caries are caused by both direct and indirect effects of radiotherapy.32 The main factor, hyposalivation, leads to loss of pH buffer, acidification of the oral environment and acceleration of demineralization in a specific pattern. Secondarily, radiation damages dentinal tubules, which could explain why lesions develop at the dentin-enamel border near the cementoenamel junction. Dental considerations: ■ Rigorous oral hygiene needs to be maintained throughout treatment, including use of high-concentration fluoride (5000 ppm) dentifrice and daily application of 1.0% sodium fluoride gel via custom fluoride trays. However, some patients may not be able to tolerate use of fluoride trays due to severity of mucositis. In this case, the patient can be advised to wait until recovery from mucositis before fluoride treatment. ■ Recommend diet counseling to help patients maintain a noncariogenic diet low in sugar. ■ Regular and frequent dental evaluations (every three months) should be maintained after completion of treatment to monitor caries risk. Osteoradionecrosis Osteoradionecrosis (ORN) is a common but severe complication of radiation therapy (as well as major surgical resections) that can present years following treatment. Recent published data reported that between 5% to 20% of patients with head and neck cancer who underwent radiation therapy developed ORN following 244 APRIL

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completion of treatment.33,34 The classic clinical presentation is a patient with a history of radiation to the head and neck region who presents with a region of exposed bone (FIGURE 1C ) after a dental extraction. The clinical presentation ranges from a stable and asymptomatic area of exposed bone to necrotic bone causing severe pain. The pathogenesis of ORN is thought to be due to radiation damage of the alveolar bone leading to hypocellularity of bone marrow and ultimately hypoxia causing

Osteoradionecrosis (ORN) is a common but severe complication of radiation therapy (as well as major surgical resections) that can present years following treatment. delayed wound healing.35 Trauma, surgery or dental extraction in a patient with a history of radiation can increase the risk of developing ORN following head and neck radiation. Management of ORN depends on the severity of disease. For localized exposed bone without any surrounding inflammation, purulence or systemic infection, treatment includes chlorhexidine 0.12% oral rinses (twice daily). Systemic antibiotics are recommended in addition to chlorhexidine 0.12% rinses for patients with exposed bone and surrounding inflammation, purulence and/or systemic infection. Surgical debridement and/or resection with reconstruction may be considered for cases that are refractory to conservative treatment or have a risk for developing pathologic fractures.

Hyperbaric oxygen (HBO) has been proposed as a potential treatment for ORN due to its hypothesized ability to increase angiogenesis and osteoblastic proliferation in irradiated tissues. The role of HBO for ORN has been contested in the literature because of its varying clinical effectiveness, limited availability of treatment centers, number and duration of visits (typically 20 sessions before extraction and 10 following) and high costs.36–38 While not considered a first-line treatment, some centers still propose the use of HBO as an adjunctive therapy in high-risk cases where the patient failed to respond to both conservative treatment and surgical resection. It should be noted that in patients undergoing concurrent chemotherapy or who present with untreated pneumothorax, COPD or pulmonary nodules, HBO should be avoided. There is ongoing debate about the role of HBO in promoting the growth and metastases of existing tumors.39,40 Novel treatments such as pentoxifylline and vitamin E (PENTOCLO) are currently undergoing clinical trials, but further research is needed to validate the therapeutic benefits.40,41 Dental considerations: ■ The goal of the pretreatment dental evaluation is to minimize the risk of oral complications during treatment; provide medically necessary dental care; and ensure initiation of radiation therapy without delay. ■ Medically necessary dental care includes the following: • Teeth that are likely to become a source of infection later on should be treated prior to radiation therapy with either restorative procedures, endodontics, periodontal therapy or extraction. In general, dental

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extractions should be considered for teeth with poor prognosis or acute infections only, because extractions performed on teeth prior to treatment can be a risk factor for the development of ORN subsequently.34 • For teeth with good restorative prognosis (incipient caries, teeth requiring uncomplicated endodontic treatment, mild periodontal disease), consider nonsurgical interventions first. ■ Following radiation therapy, the goal of dental treatment is to maintain a stable dentition to prevent infections, which is a major risk factor for the development of ORN. For infected teeth with poor restorative prognosis, a preferred alternative to dental extraction includes root canal therapy along with decoronation and placement of a permanent restoration over the exposed root surface. However, for infected teeth with poor endodontic prognosis, extraction may be necessary. In these cases, conservative surgical technique (avoid raising a gingival flap and removing supporting alveolar bone) should be utilized along with prescription topical and systemic antibiotics to reduce risk of postoperative infections. Additionally, a follow-up appointment two weeks after the extraction is appropriate to ensure proper healing. Trismus Radiation of the head and neck region can cause fibrosis of the temporomandibular joint (TMJ) and the muscles of mastication, leading

to trismus. The incidence of trismus following head and neck radiation has been reported to be up to 45%, with those receiving more than 60 Gy of cumulative radiation more likely to experience trismus.42,43 The onset of radiation-induced trismus typically presents toward the end of treatment or even years after treatment.44 Trismus can have a significant health impact such as compromised nutrition from difficulty of mastication, impaired speech and difficulty maintaining oral hygiene. Severity of symptoms depends

Unlike nociceptive pain, neuropathic pain does not respond well to typical treatment and is more difficult to manage effectively.

on the dose and fields of radiation, but if the radiation field includes the TMJ or muscles of mastication, trismus should be anticipated. Management starts with prevention. During the course of radiotherapy, the “three-finger test” is an easy method of monitoring the initial signs of trismus. The ability to insert three fingers into the mouth roughly indicates a normal maximum incisal opening (MIO). Post-treatment, the management of trismus includes incorporating daily jaw stretching exercises with a range of dental appliances such as TheraBite or Dynasplint that are designed to increase or maintain MIO.44 Alternatively, patients can be advised to use tongue blades or clean fingers to gently apply forced pressure to achieve the same

effect as dental appliances. Other management options may include surgery, botulinum injections, pentoxifylline and photobiomodulation.45 Dental considerations: ■ Trismus can compromise patients’ ability to practice home care effectively, increasing their caries risk, and may increase the difficulty of receiving dental treatment during long appointments, potentially compromising the quality of care. ■ Conservative therapy, including heat compresses, passive stretching exercise, NSAIDs, trigger-point injections and botulinum toxin may be an effective treatment for pain and spasms associated with the TMJ and surrounding muscles.46,47 Radiotherapy-Related Neuropathic Pain Neuropathic pain is defined as pain initiated by neural injury. Neuropathic pain can often follow or be triggered by prolonged onset of nociceptive pain or pain as a result of noxious stimuli. Unlike nociceptive pain, neuropathic pain does not respond well to typical treatment and is more difficult to manage effectively.48 Radiotherapy-related neuropathic pain, a late treatment complication, is estimated to affect 30% of head and neck cancer patients with varying severity.49 Onset can be as late as decades after radiotherapy, making diagnosis particularly difficult. Some cases may be associated with oral dysesthesia/ burning mouth syndrome, contributed by major life stressors, anxiety, posttraumatic stress and depression.50 While the pathogenesis is not entirely understood, radiotherapy-related neuropathic pain is thought to be caused by direct injury to cranial or peripheral nerves, ischemia due to microvascular damage and indirect nerve compression APRIL 2 0 2 1

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TABLE 1

Management Guidelines for Invasive Dental Procedures During Cancer Treatment Medical status

Guideline

Comments

Neutrophils > 2000/mm3

No prophylactic antibiotic needed.

platelet count < 100,000/µL and is more commonly seen in patients undergoing allogenic HCT as compared to OC/OP < 1,000/mm3 Amikacin 150 mg/m² 1h presurgery; ticarcillin 75 mg/kg IV ½ h prior to cancers.57 The biggest concern related to surgery; repeat 6h post-surgery. CIT is risk of bleeding. At platelet counts of < 50,000/µL, bleeding risk is increased Platelets 3 during surgical interventions, and at > 60,000/mm No additional support. a count of < 10,000/µL, spontaneous Utilize techniques to promote 30,000–60,000/mm³ Platelet transfusions are optional hemorrhage can occur.54 CIT not only establishing and maintaining control for noninvasive treatment; consider increases patient morbidity, but also of bleeding (i.e., sutures, pressure administering preoperatively and packs, minimize trauma). 24h later for surgical treatment the number of hospital admissions. (e.g., dental extractions). Additional One retrospective cohort study found transfusions are based on clinical that the incidence of CIT is 9.7% course. during the course of chemotherapy, and In addition to above, consider using < 30,000/mm³ Platelets should be transfused one-third of those incidents resulted hemostatic agents (i.e., microfibrillar 1h before procedure; obtain an in a hospital admission with a mean collagen, topical thrombin). immediate post-infusion platelet cost of $36,448 per admission.55 count; transfuse regularly to maintain Aminocaproic acid may help stabilize counts > 30,000–40,000/mm³ until nondurable clots. Monitor sites Dental considerations: carefully. initial healing has occurred. In some ■ Consult the patient’s oncologist instances, platelet counts > 60,000/ before any dental procedure. mm³ may be required. • Prior to oral surgery or any Retrieved from NCI PDQ Oral Complications of Chemotherapy and Head/Neck Radiation. Bethesda, Md.: National invasive procedures, bloodwork Cancer Institute. Updated Dec. 16, 2016. should be ordered by the oncologist to confirm the platelet count. Refer to TA BLE 1 from radiation-induced tissue candidiasis, are commonly seen in patients 51 for management guidelines for fibrosis. Management of neuropathic undergoing chemotherapy because of a invasive dental procedures pain includes use of non-opioid combination of xerostomia and mucosal during cancer treatment to best analgesics, benzodiazepines, tricyclic injury. Management includes use of 52 minimize risk of bleeding. antidepressants and anti-epileptics. perioperative antibiotics and antifungals for ■ Intraoperatively, local hemostatic patients who are at high risk of infection. agents such as pressure gauze, Chemotherapy Dental considerations: oxidized cellulose (Surgicel), Infection ■ Before any dental procedure, consult absorbable gelatin powder Cytotoxic chemotherapeutic agents can the patient’s oncologist about the (Gelfoam) and oral anticause prolonged neutropenia in patients need for perioperative antibiotics. fibrinolytics (tranexamic undergoing treatment. Because neutrophils ■ Prior to oral surgery or any invasive mouthwash/Amicar) can be used are important for providing host defense procedures, bloodwork should be as indicated to control bleeding. against pathogens, the risk of infection ordered by the oncologist to confirm 53 Additionally, electrocautery increases with the degree of neutropenia. the absolute neutrophil count devices and bone wax can also be As described previously in the radiotherapy (ANC). Refer to TA BLE 1 for used to mitigate excess bleeding. section, patients undergoing management guidelines for invasive chemoradiotherapy often develop oral dental procedures during cancer Immunotherapy (PD-1, PD-L1 mucositis, which breaks down the lining of treatment to best minimize risk mucosa, further increasing the risk of of infection. inhibitors) and Targeted Therapy infection. Bacterial infections are most (EGFR inhibitor, cetuximab, MAB, common in patients with periodontal Bleeding (Thrombocytopenia) TK inhibitors) Because immunotherapeutic agents disease and receiving high-dose Chemotherapy-induced work by upregulating the immune chemotherapy. Fungal infections, including thrombocytopenia (CIT) is defined as 1,000–2,000/mm

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AHA prophylactic antibiotic recommended (low risk).

No clear guideline. Defer to clinical judgment.

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system to fight cancer cells, a side effect is the loss of self-antigen tolerance and autoimmune mediated toxicities.56 Oral immune-related toxicities (FIGURE 1D ) include lichenoid reaction, erythema multiforme and vesiculobullous disorders.11,12 Management of oral irAEs includes topical corticosteroids, such as dexamethasone solution, clobetasol gel and systemic steroids, such as prednisone.

Surgery

While surgery is a mainstay in the treatment of OC/OP cancers, many factors need to be taken into consideration to weigh the balance between increasing patient survival and resulting morbidities that impact quality of life. The biggest morbidities to consider include facial disfigurement, neuropathies, malocclusion and functional deficiencies resulting in difficulties swallowing, speech disorders and impaired mastication. Management includes reconstructive surgery of both hard and soft tissue to restore function and aesthetics, utilization of maxillofacial prosthesis and speech and physical therapy to rehabilitate patients.

Dental Guidelines for Patients With OC/OP Cancer

Continued improvements in treatment methods for OC/OP cancers have increased the average life expectancy after diagnosis. However, the sequelae of oral complications following treatment for OC/OP cancers is complex and often has a significant impact on patients’ quality of life. Dental providers have an important role in the management of patient oral health before, during and following treatment for OC/OP cancers. Currently, few comprehensive dental guidelines exist for the management of oral complications of OC/OP cancer

treatment.19,57–59 Therefore, drawing on our institutional knowledge and recommendations from experienced practitioners, we propose the following practical approaches to help dental providers manage the oral health needs of patients before, during and after treatment for OC/OP cancers. (TA BLE 2 )

Pretreatment

The National Cancer Institute recommends that patients visit their dentist for a comprehensive evaluation four weeks (or longer) prior to the start of

Continued improvements in treatment methods for OC/ OP cancers have increased the average life expectancy after diagnosis.

treatment. The goal of the pretreatment dental evaluation is to minimize the risk of complications during treatment and to ensure there is no delay in cancer therapy initiation. A thorough health history should be taken to assess the patient’s general health as well as a smoking and alcohol history. Patients with OC/ OP cancer who are smokers should be advised to stop smoking to decrease their risk of developing recurrent cancers. A full-mouth series of radiographs should be taken (unless taken within the last six months) and a thorough examination performed to rule out periodontal disease, tooth decay and infection of previously endodontically treated teeth and third molars. Any teeth that are likely to become a source of infection later on should be treated either with

restorative dentistry, endodontic therapy, periodontal therapy or extraction. Absolute indications for dental extraction: ■ Persistent periapical infection refractory to endodontic treatment. ■ Nonrestorable carious teeth. ■ Teeth with advanced, irreversible periodontal involvement (Grade III mobility, Class III furcation involvement). ■ Partially impacted teeth with/ without signs of pericoronitis. ■ Supra-erupted teeth with potential of causing trauma to the opposing mucosa. Relative indications for dental extraction where conservative treatment is advised: ■ Teeth with pulpal involvement that can be treated with endodontics. ■ Restorable carious teeth. ■ Teeth with gingivitis or mild or moderate periodontal involvement. A dental prophylaxis should be performed if the patient has not had one within the last three months. Finally, oral hygiene instructions should be given with the goal of maintaining stable dentition and preventing infections that could interfere with cancer therapy. Patients with extensive restorations such as implants, fixed prosthesis or dentures should take extra care to maintain excellent oral hygiene during treatment in order to minimize the need for removal of these restorations. Supplemental fluoride should be prescribed to reduce patients’ caries risk during treatment.

During Treatment

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TABLE 2

Summary of Dental Guidelines of Oral Complications Associated With OC/OP Cancers Treatment Oral complication

Dental guideline

Oral mucositis

• Recommend patients maintain excellent oral hygiene to prevent infections, including brushing with a soft toothbrush and fluoridated toothpaste, flossing and using nonmedicated mouthwashes (saline or sodium bicarbonate rinse) to promote oral clearance. • Agents for symptomatic relief: ∘ Analgesic mouthwash such as lidocaine 2% oral solution. ∘ Mucoadhesive agents such as Gelclair (Fortovia Therapeutics Inc., Raleigh, N.C.). ∘ Topical tricyclic antidepressant, doxepin oral solution. ∘ Supersaturated calcium phosphate solution (Caphosol) solution.

Hyposalivation/xerostomia

• Encourage patients to hydrate more often to help alleviate symptoms of xerostomia. Drink 40 ounces of water per day and minimize caffeine intake. • Use of pharmacologic sialagogues such as pilocarpine may help patients with residual salivary gland function to increase saliva production. • Counsel patients to avoid smoking and drinking alcohol. • Agents for symptomatic relief: ∘ Salivary stimulants such as sugarless lozenges or chewing gum. ∘ Saliva substitutes such as ACT, Biotène, Mouth Kote, Oasis Moisturizing Mouth Spray, Xylimelts, Xerostom or other formulations containing carboxymethylcellulose.

Radiation caries

• Patients should be instructed to use high-concentration fluoride (5,000 ppm) dentifrice and apply fluoride gel daily via custom fluoride trays. • Patients should also receive nutritional counseling to maintain a balanced, noncariogenic diet low in sugar. • Regular and frequent dental evaluation (every three months) to monitor caries risk.

Osteoradionecrosis

• In general, avoid dental extractions in patients with history of radiation to the head and neck if possible. For teeth with poor prognosis, the goal is to eliminate the source of infection. For teeth with pulpal involvement, root canal therapy should be the first line of treatment. • When extraction is necessary, conservative surgical technique should be utilized along with prescription of prophylactic antibiotics to reduce risk of postoperative infections.

Trismus

• Conservative therapy, including heat compresses, passive stretching exercise, NSAIDs, trigger-point injections and botulinum toxin, may be an effective treatment for pain and spasms associated with TMJ and surrounding muscles. • Recommend patients incorporate daily jaw stretching exercises with a range of dental appliances such as TheraBite or Dynasplint that are designed to increase or maintain MIO. Alternatively, patients can be advised to use tongue blades or clean fingers to gently apply forced pressure to achieve the same effect as dental appliances.

Infection

• A comprehensive dental evaluation should be completed one month prior to the start of chemoradiotherapy with the goal of eliminating any potential sources of infection that may occur during treatment. • Preoperatively, prior to oral surgery or any invasive procedures, blood work should be ordered by the oncologist to confirm the absolute neutrophil count (ANC).

Bleeding

• Preoperatively, prior to oral surgery or any invasive procedures, bloodwork should be ordered by the oncologist to confirm platelet count. • Intraoperatively, local hemostatic agents such as pressure gauze, oxidized cellulose (Surgicel), absorbable gelatin powder (Gelfoam) and oral antifibrinolytics (TXA mouthwash/Amicar) can be used as indicated to control bleeding. • Cauterization and bone wax can also be used to mitigate excess bleeding.

complications are usually addressed in a hospital setting. Please refer to the guidelines from the Physician’s Data Query/National Cancer Institute listed in TA BLE 1 for management of potential infection and/or bleeding risk.

Post-treatment

Following the completion of treatment, patients require close dental surveillance. A routine exam with hygiene should be performed every three to four months to monitor caries risk and screen for recurrent malignancies. Fluoride 248 APRIL

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treatments should be continued due to patients’ elevated caries risk. Patients should also be counseled on nutritional guidelines, including maintaining a noncariogenic diet low in sugar.

for whom removable prostheses are not an option, implants may be attempted as long as patients are informed of the increased risk of implant failure, risk of developing ORN and the need for continued close follow-up.

Restorative Considerations

Conclusion

A number of studies have been done on the survival of implants in irradiated jaws, showing that there is a high risk of implant failure compared to nonirradiated jaws.60–62 As such, preference is given to the use of removable prosthetics to replace missing hard and soft tissues. However, in patients

Dental providers play a key role in the preparation of a healthy mouth, minimizing the risk of developing oral complications during and after the course of cancer therapy. It is a good practice for the dental provider to coordinate closely with the oncology team in ensuring dental needs

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are met to prevent any unforeseen delay in the start of cancer treatment. This is a role that dental providers will encounter more during their careers, attributed by the increasing number of cancer survivors. n RE FEREN CE S 1. The American Cancer Society. Key Statistics for Oral Cavity and Oropharyngeal Cancers, 2020. www.cancer.org/cancer/ oral-cavity-and-oropharyngeal-cancer/about/key-statistics.html. 2. Senkomago V, Henley SJ, Thomas CC, et al. Human Papillomavirus-Attributable Cancers — United States, 2012– 2016. MMWR Morb Mortal Wkly Rep 2019;68(33): 724–28. 3. Ellington TD, Henley SJ, Senkomago V, et al. Trends in incidence of cancers of the oral cavity and pharynx — United States 2007–2016. MMWR Morb Mortal Wkly Rep 2020;69(15):433–38. 4. Montero PH, Patel SG. Cancer of the oral cavity. Surg Oncol Clin N Am 2015 Jul;24(3):491–508. doi: 10.1016/j. soc.2015.03.006. Epub 2015 Apr 15. 5. Chera BS, Amdur RJ, Green R, et al. Phase II trial of de-intensified chemoradiotherapy for human papillomavirusassociated oropharyngeal squamous cell carcinoma. J Clin Oncol 2019 Oct 10;37(29):2661–2669. doi: 10.1200/ JCO.19.01007. Epub 2019 Aug 14. 6. Hargreaves S, Beasley M, Hurt C, Jones TM, Evans M. Deintensification of adjuvant treatment after transoral surgery in patients with human papillomavirus-positive oropharyngeal cancer: The conception of the PATHOS study and its development. Front Oncol 2019 Oct 1;9:936. doi: 10.3389/ fonc.2019.00936. eCollection 2019. 7. National Comprehensive Cancer Network. NCCN Practice Guidelines in Oncology: Head and Neck Cancers version 2.2013. jnccn.org/view/journals/jnccn/11/8/article-p917. xml. 8. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 2019 Nov 23;394(10212):1915–1928. doi: 10.1016/S01406736(19)32591-7. Epub 2019 Nov 1. 9. Mendenhall WM, Dagan R, Bryant CM, Fernandes RP. Radiation oncology for head and neck cancer: Current standards and future changes. Oral Maxillofac Surg Clin North Am 2019 Feb;31(1):31–38. doi: 10.1016/j. coms.2018.08.003. Epub 2018 Oct 25. 10. Yeh S-A. Radiotherapy for head and neck cancer. Semin Plast Surg 2010 May;24(2):127–36. doi: 10.1055/s-00301255330. 11. Shazib MA, Woo S-B, Sroussi H, et al. Oral immunerelated adverse events associated with PD-1 inhibitor therapy: A case series. Oral Dis 2020 Mar;26(2):325–333. doi: 10.1111/odi.13218. Epub 2020 Jan 9. 12. Sibaud V, Meyer N, Lamant L, et al. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol 2016 Jul;28(4):254–63. doi: 10.1097/CCO.0000000000000290. 13. Vera-Llonch M, Oster G, Hagiwara M, Sonis S. Oral

mucositis in patients undergoing radiation treatment for head and neck carcinoma. Cancer 2006 Jan 15;106(2):329–36. doi: 10.1002/cncr.21622. 14. Moslemi D, Nokhandani AM, Otaghsaraei MT, et al. Management of chemo/radiation-induced oral mucositis in patients with head and neck cancer: A review of the current literature. Radiother Oncol 2016 Jul;120(1):13–20. doi: 10.1016/j.radonc.2016.04.001. Epub 2016 Apr 21. 15. Elad S, Zadik Y. Chronic oral mucositis after radiotherapy to the head and neck: A new insight. Support Care Cancer 2016 Nov;24(11):4825–30. doi: 10.1007/s00520-0163337-5. Epub 2016 Jul 30. 16. Lalla RV, Treister N, Sollecito T, et al. Oral complications at six months after radiation therapy for head and neck cancer. Oral Dis 2017 Nov;23(8):1134–1143. doi: 10.1111/ odi.12710. Epub 2017 Aug 3. 17. Rosenthal DI, Trotti A. Strategies for managing radiation-induced mucositis in head and neck cancer. Semin Radiat Oncol 2009 Jan;19(1):29–34. doi: 10.1016/j. semradonc.2008.09.006. 18. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer 2004 Apr;4(4):277–84. doi: 10.1038/nrc1318. 19. Sroussi HY, Epstein JB, Bensadoun R-J, et al. Common oral complications of head and neck cancer radiation therapy: Mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease and osteoradionecrosis. Cancer Med 2017 Dec;6(12):2918– 2931. doi: 10.1002/cam4.1221. Epub 2017 Oct 25. 20. Elting LS, Chang YC. Costs of oral complications of cancer therapies: Estimates and a blueprint for future study. J Natl Cancer Inst Monogr 2019 Aug 1;2019(53):lgz010. doi: 10.1093/jncimonographs/lgz010. 21. Bensinger W, Schubert M, Ang KK, et al. NCCN Task Force report. Prevention and management of mucositis in cancer care. J Natl Compr Canc Netw 2008;6 Suppl 1:S1–21; quiz S22-4. 22. Sonis S. Pathobiology of oral mucositis: Novel insights and opportunities. J Support Oncol 2007 Oct;5(9 Suppl 4):3–11. 23. Zhu X-X, Yang X-J, Chao Y-L, et al. The potential effect of oral microbiota in the prediction of mucositis during radiotherapy for nasopharyngeal carcinoma. EBioMedicine 2017 Apr;18:23–31. doi: 10.1016/j.ebiom.2017.02.002. Epub 2017 Feb 7. 24. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004 Dec 16;351(25):2590–8. doi: 10.1056/ NEJMoa040125. 25. Anderson CM, Lee CM, Saunders DP, et al. Phase IIb, randomized, double-blind trial of gc4419 versus placebo to reduce severe oral mucositis due to concurrent radiotherapy and cisplatin for head and neck cancer. J Clin Oncol 2019 Dec;37(34):3256–65. doi: 10.1200/JCO.19.01507. 26. Chao KSC, Majhail N, Huang CJ, et al. Intensitymodulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: A comparison with conventional techniques. Radiother Oncol 2001 Dec;61(3):275–80. doi: 10.1016/s0167-8140(01)00449-2. 27. Panarese V, Majid Moshirfar. Pilocarpine. Treasure Island, FL: StatPearls Publishing; 2020. 28. Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine as a radioprotector in head and

neck cancer. J Clin Oncol 2000 Oct 1;18(19):3339–45. doi: 10.1200/JCO.2000.18.19.3339. 29. Jellema AP, Slotman BJ, Muller MJ, et al. Radiotherapy alone, versus radiotherapy with amifostine 3 times weekly, versus radiotherapy with amifostine five times weekly. Cancer 2006 Aug 1;107(3):544–53. doi: 10.1002/cncr.22020. 30. Ranganathan K, Simon E, Lynn J, et al. Novel formulation strategy to improve the feasibility of amifostine administration. Pharm Res 2018 Mar 19;35(5):99. doi: 10.1007/s11095018-2386-5. 31. Fischer DJ, Epstein JB. Management of patients who have undergone head and neck cancer therapy. Dent Clin North Am 2008 Jan;52(1):39–60, viii. doi: 10.1016/j. cden.2007.09.004. 32. Gupta N, Pal M, Rawat S, et al. Radiation-induced dental caries, prevention and treatment — a systematic review. Natl J Maxillofac Surg Jul–Dec 2015;6(2):160–6. doi: 10.4103/0975-5950.183870. 33. Dong Y, Ridge JA, Li T, et al. Long-term toxicities in 10-year survivors of radiation treatment for head and neck cancer. Oral Oncol Aug;71:122–128. doi: 10.1016/j. oraloncology.2017.05.009. Epub 2017 Jun 23. 34. Moon DH, Moon SH, Wang K, et al. Incidence of, and risk factors for, mandibular osteoradionecrosis in patients with oral cavity and oropharynx cancers. Oral Oncol 2017 Sep;72:98–103. doi: 10.1016/j.oraloncology.2017.07.014. Epub 2017 Jul 16. 35. Rivero JA, Shamji O, Kolokythas A. Osteoradionecrosis: A review of pathophysiology, prevention and pharmacologic management using pentoxifylline, a-tocopherol and clodronate. Oral Surg Oral Med Oral Pathol Oral Radiol 2017 Nov;124(5):464–471. doi: 10.1016/j.oooo.2017.08.004. Epub 2017 Aug 23. 36. Ceponis P, Keilman C, Guerry C, Freiberger J. Hyperbaric oxygen therapy and osteonecrosis. Oral Dis 2017 Mar;23(2):141–151. doi: 10.1111/odi.12489. Epub 2016 May 27. 37. Sultan A, Hanna GJ, Margalit DN, et al. The use of hyperbaric oxygen for the prevention and management of osteoradionecrosis of the jaw: A Dana-Farber/Brigham and Women’s Cancer Center multidisciplinary guideline. Oncologist 2017 Mar;22(3):343–350. doi: 10.1634/ theoncologist.2016-0298. Epub 2017 Feb 16. 38. Gawdi R, Cooper JS. Hyperbaric Contraindications. Treasure Island, Fla.:StatPearls Publishing; 2020. www.ncbi. nlm.nih.gov/books/NBK557661. 39. Feldmeier J, Carl U, Hartmann K, Sminia P. Hyperbaric oxygen: Does it promote growth or recurrence of malignancy? Undersea Hyperb Med Spring 2003;30(1):1–18. 40. Dissard A, Dang NP, Barthelemy I, et al. Efficacy of pentoxifylline-tocopherol-clodronate in mandibular osteoradionecrosis. Laryngoscope 2020 Nov;130(11):E559– E566. doi: 10.1002/lary.28399. Epub 2019 Nov 20. 41. Breik O, Tocaciu S, Briggs K, Tasfia Saief S, Richardson S. Is there a role for pentoxifylline and tocopherol in the management of advanced osteoradionecrosis of the jaws with pathological fractures? Case reports and review of the literature. Int J Oral Maxillofac Surg 2019 Aug;48(8):1022– 1027. doi: 10.1016/j.ijom.2019.03.894. Epub 2019 Apr 10. 42. Louise Kent M, Brennan MT, Noll JL, et al. Radiationinduced trismus in head and neck cancer patients. Support Care Cancer 2008 Mar;16(3):305–9. doi: 10.1007/ APRIL 2 0 2 1

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s00520-007-0345-5. Epub 2007 Oct 27. 43. Teguh DN, Levendag PC, Voet P, et al. Trismus in patients with oropharyngeal cancer: Relationship with dose in structures of mastication apparatus. Head Neck 2008 May;30(5):622– 30. doi: 10.1002/hed.20760. 44. Bensadoun RJ, Riesenbeck D, Lockhart PB, et al. A systematic review of trismus induced by cancer therapies in head and neck cancer patients. Support Care Cancer 2010 Aug;18(8):1033–8. doi: 10.1007/s00520-010-0847-4. Epub 2010 Mar 6. 45. Dijkstra PU, Kalk WWI, Roodenburg JLN. Trismus in head and neck oncology: A systematic review. Oral Oncol 2004 Oct;40(9):879–89. doi: 10.1016/j. oraloncology.2004.04.003. 46. Kim H-S, Yun P-Y, Kim Y-K. A clinical evaluation of botulinum toxin-A injections in the temporomandibular disorder treatment. Maxillofac Plast Reconstr Surg 2016 Jan 28;38(1):5. doi: 10.1186/s40902-016-0051-7. eCollection 2016 Dec. 47. Gil-Martínez A, Paris-Alemany A, López-de-UraldeVillanueva I, La Touche R. Management of pain in patients with temporomandibular disorder (TMD): Challenges and solutions. J Pain Res 2018 Mar 16;11:571–587. doi: 10.2147/JPR. S127950. eCollection 2018. 480. Epstein JB, Hong C, Logan RM, et al. A systematic review of orofacial pain in patients receiving cancer therapy. Support Care Cancer 2010 Aug;18(8):1023–31. doi: 10.1007/ s00520-010-0897-7. Epub 2010 Jun 11. 49. Grond S, Zech D, Lynch J, et al. Validation of World Health Organization guidelines for pain relief in head and neck cancer. A prospective study. Ann Otol Rhinol Laryngol 1993 May;102(5):342–8. doi: 10.1177/000348949310200504. 50. Ritchie A, Kramer JM. Recent advances in the etiology and treatment of burning mouth syndrome. J Dent Res 2018 Oct;97(11):1193–1199. doi: 10.1177/0022034518782462. Epub 2018 Jun 18. 51. Delanian S, Lefaix J-L, Pradat P-F. Radiation-induced neuropathy in cancer survivors. Radiother Oncol 2012 Dec;105(3):273–82. doi: 10.1016/j.radonc.2012.10.012. 52. Jiang J, Li Y, Shen Q, et al. Effect of pregabalin on radiotherapy-related neuropathic pain in patients with head and neck cancer: A randomized controlled trial. J Clin Oncol 2019 Jan 10;37(2):135–143. doi: 10.1200/ JCO.18.00896. Epub 2018 Nov 20. 53. Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol 2018;36(30):3043–54. 54. DJ K. General aspects of thrombocytopenia, platelet transfusions and thrombopoietic growth factors. In: Kitchens C, Kessler CMC, Konkle B, eds. Consultative Hemostasis and Thrombosis. Philadelphia: Elsevier; 2013. 55. Weycker D, Hatfield M, Grossman A, et al. Risk and consequences of chemotherapy-induced thrombocytopenia in U.S. clinical practice. BMC Cancer 2019 Feb 14;19(1):151. doi: 10.1186/s12885-019-5354-5. 56. Connolly C, Bambhania K, Naidoo J. Immune-related adverse events: A case-based approach. Front Oncol 2019 Jun 20;9:530. doi: 10.3389/fonc.2019.00530. eCollection 2019. 57. Epstein JB, Thariat J, Bensadoun R-J, et al. Oral complications of cancer and cancer therapy. CA Cancer J Clin

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Nov–Dec 2012;62(6):400–22. doi: 10.3322/caac.21157. Epub 2012 Sep 12. 58. Elad S, Cheng KKF, Lalla RV, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 2020 Oct 1;126(19):4423–4431. doi: 10.1002/cncr.33100. Epub 2020 Jul 28. 59. Yarom N, Shapiro CL, Peterson DE, et al. Medicationrelated osteonecrosis of the jaw: MASCC/ISOO/ ASCO clinical practice guideline. J Clin Oncol 2019 Sep 1;37(25):2270–2290. doi: 10.1200/JCO.19.01186. Epub 2019 Jul 22. 60. Koudougou C, Bertin H, Lecaplain B, et al. Postimplantation radiation therapy in head and neck cancer patients: Literature review. Head Neck 2020 Apr;42(4):794–802. doi: 10.1002/hed.26065. Epub 2020 Jan 3. 61. Chambrone L, Mandia J Jr., Shibli JA, Romito GA, Abrahao M. Dental implants installed in irradiated jaws: A systematic review. J Dent Res 2013 Dec;92(12 Suppl):119S–30S. doi: 10.1177/0022034513504947. Epub 2013 Oct 24. 62. Schmitt CM, Buchbender M, Lutz R, Neukam FW. Oral implant survival in patients with bisphosphonate (BP)/ antiresorptive and radiation therapy and their impact on osteonecrosis of the jaws. A systematic review. Eur J Oral Implantol 2018;11 Suppl 1:S93–s111. T H E CO RRE S P ON DIN G AU T HOR , Muhammad Ali Shazib, DMD, can be reached at ali_shazib@unc.edu.

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The Effectiveness of Diode Laser Therapy With Scaling/Root Planing in Treating Periodontitis Joseph Zingale, DDS, MPS; Navid Knight, DDS; Miriam Robins, DDS, MS; Lisa Harpenau, DDS, MS, MBA, MA; William Lundergan, DDS, MA; and David Chambers, PhD, MEd, MBA

abstract Background: The effectiveness of scaling/root planing (SRP) plus 1064 wavelength diode laser therapy was compared to scaling/root planing only in treating moderate-severe (stages II–III) chronic periodontitis. Methods: Twenty-two subjects meeting all inclusion/exclusion criteria completed the study. Subjects had at least one experimental (SRP+LASER) and one control (SRP-ONLY) site randomly selected. Pre- and post-treatment clinical crown lengths (CCL), probing depths (PD) and bleeding on probing (BOP) were recorded by an examiner blinded to treatment. Bone levels were evaluated pre- and post-treatment using cone beam computed tomography. Results: Repeated measures ANOVA and t-tests were used for analysis. There were no statistically significant differences (p > 0.05) in pretreatment CCL, PD, BOP and interproximal bone height between treatment groups. In post-treatment, there were no statistically significant differences in mean changes between treatment groups (p > 0.05) for CCL, PD and BOP except for bone fill, which significantly increased for the SRP+LASER group (p = 0.002) compared to the SRP-ONLY group. Conclusions and practical implications: The adjunct use of a 1064 wavelength diode laser with definitive SRP therapy was significantly more effective (p = 0.002) than SRP alone evidenced by an increase in post-treatment bone fill. Both therapies reduced PD and BOP with minimal effect on CCL. Adjunct laser therapy may be another useful tool in the clinician’s armamentarium for managing periodontitis. Further scientific research is warranted, such as a larger scale study, greater long-term follow-up and the addition of another study arm: a comparison to surgical pocket reduction therapy. Key words: Laser, periodontal therapy, diode laser, periodontitis, cone beam computed tomography

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AUTHORS Joseph Zingale, DDS, MPS, is a professor of periodontics at the University of the Pacific, Arthur A. Dugoni School of Dentistry in San Francisco. He is board certified. Conflict of Interest Disclosure: None reported. Navid Knight, DDS, is an assistant professor of periodontics at the University of the Pacific, Arthur A. Dugoni School of Dentistry in San Francisco. Conflict of Interest Disclosure: None reported. Miriam Robins, DDS, MS, is an assistant professor of oral and maxillofacial radiology at the University of the Pacific, Arthur A. Dugoni School of Dentistry in San Francisco. She is board certified. Conflict of Interest Disclosure: None reported.

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Lisa Harpenau, DDS, MS, MBA, MA, is a professor of periodontics at the University of the Pacific, Arthur A. Dugoni School of Dentistry in San Francisco. Conflict of Interest Disclosure: None reported. William Lundergan, DDS, MA, is professor and chair of periodontics at the University of the Pacific Arthur A. Dugoni School of Dentistry in San Francisco. Conflict of Interest Disclosure: None reported. David Chambers, PhD, MEd, MBA, is a professor of orthodontics at the University of the Pacific, Arthur A. Dugoni School of Dentistry in San Francisco. Conflict of Interest Disclosure: None reported.

here is increasing interest in laser therapy as either an adjunct or replacement for conventional periodontal therapy. The prospect of minimal post-treatment pain and no sutures has widespread public appeal. In addition, there appears to be only minor alterations in crown length and gingival architecture with laser therapy, resulting in a cosmetic benefit.1 The diode laser has gained in popularity because of its lower cost and ability to produce an almost blood-free surgical field. It can be used for minor crown lengthening, gingivectomy and gingivoplasties, gingival retraction prior to impression taking, aesthetic crown lengthening, labial and lingual frenum relief, biopsy removal and soft tissue gingival curettage.2,3 The diode laser easily removes the ulcerated and inflamed epithelial lining (curettage) and greatly reduces the pathogenic organisms (disinfection) but is not useful for calculus removal.4–7 If the diode laser is used with proper caution, injury to adjacent root surfaces is minimized and calculus removal is readily accomplished using ultrasonic and hand instruments. Calculus can be removed by using hard tissue lasers, but great care must be exercised so as not to overheat root surfaces, making them less biologically compatible for proper healing.8–10 Probing depths exceeding 5 mm are difficult to maintain, as complete calculus removal may be less than 40%.11,12 In many instances, antibiotics and antimicrobial medications are placed in the gingival sulcus to reduce the level of pathogenic organisms and enhance healing. The diode laser provides a medication-free alternative to reduce pathogenic organisms during therapy.5,13–18 The ability to curet

in a blood-free surgical field further enhances the clinician’s ability to remove offending root deposits. Biostimulatory effects with low-level laser exposure has led to increased interest in regenerative potentials within the soft and hard tissues of the periodontium.19–22 The 1064 XLASE (Fotona LLC, Dallas) diode laser has a longer wavelength, 1064 nm, than the conventional 810 nm diode laser and therefore has a greater depth of tissue penetration. This may further enhance biostimulation and regional disinfection, especially when pathogenic plaque biofilm organisms invade the gingival connective tissues. To assess the success of regenerative therapy on hard tissues, reentry surgery has been done to directly view the surgical field and take firsthand measurements to validate the degree of regeneration. With the advent of cone beam computed tomography (CBCT) use in dental practice, the clinician now has a noninvasive alternative for viewing dental hard tissues in multiple dimensions. The CBCT view eliminates reentry surgery, saving the clinician time and the patient an additional surgical procedure.23–26 While laser curettage along with scaling and root planing has reduced inflammation and pocket depths, the benefit that laser exposure has on the dental hard tissues and surrounding alveolar bone is uncertain. Viewing preand post-treatment CBCT scans should enhance a clinician’s ability to assess bony changes either positive or negative with a heightened degree of accuracy comparable to direct measurements observable at reentry surgery.6,27–32 The objective of this study was to investigate the effectiveness of scaling and root planing plus diode laser therapy as compared to scaling and root planing only in the treatment of moderate to severe (stages II–III)33 chronic periodontitis

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by comparing clinical crown lengths, probing depths, bleeding on probing and bone level (CBCT scans) at pretreatment and up to 18 months post-treatment.

Materials and Methods Subjects

The clinical protocol was approved by the Institutional Review Board (IRB# 17-03) at the University of the Pacific in Stockton, Calif. Inclusion criteria included being in good health and at least age 21 and having a diagnosis of moderate to severe (stages II–III)33 chronic periodontitis with at least two sites having probing depths greater than 5 mm, bleeding on gentle probing and radiographic evidence of bone loss. Subjects were excluded if they had systemic disorders such as blood cell abnormalities or HIV/AIDS, were pregnant, required antibiotic premedication for invasive dental procedures, had rampant dental caries, were undergoing orthodontic treatment, were using home bleaching trays or had an intraoral or perioral piercing. Subjects were also excluded if they were taking anticoagulants, anti-seizure medication, calcium channel blockers and/ or regularly taking medication that would interfere with the periodontal inflammatory process (e.g., ibuprofen [> 400 mg], aspirin [> 81 mg], bisphosphonates, Periostat [20 mg doxycycline hyclate bid], antibiotics or other antimicrobials). Diabetic patients, even with good control, were excluded due to potential variations in healing response. Twenty-seven subjects meeting these criteria were recruited from the recare (recall) and/or new patient population at the University of the Pacific, Arthur A. Dugoni School of Dentistry in San Francisco. A separate consent form was designed and used that explained the procedures and listed possible sequelae that could occur during treatment. Risks included those associated with root

planing and minor periodontal surgery such as transitory hot/cold sensitivity, additional space between the teeth, slight post-treatment bleeding (< 5 milliliters), possible food impaction, post-treatment infection and radiation exposure related to CBCT scans.

Study Design

The study involved seven clinical visits. The first was a pretreatment examination where at least two selected sites were randomly assigned to either the experimental, scaling and root planing

Diabetic patients, even with good control, were excluded due to potential variations in healing response.

plus laser curettage (SRP+LASER) group or the control, scaling and root planing only (SRP ONLY) group. Clinical crown lengths (CCL), probing depths (PD) and bleeding on probing (BOP) were measured using a North Carolina periodontal probe. Following the examination, certified radiologic technicians performed CBCT imaging of the appropriate sites, using a 3D Accuitomo 4 cm x 4 cm (J. Morita USA Inc., Irvine, Calif.). Bone height was measured from the alveolar crest to the cementoenamel junction (or in the case of a full-crown restoration, to the crown margin) by a board-certified oral and maxillofacial radiologist. On the second appointment, the investigator providing therapy to the randomly assigned sites confirmed and verified the areas to receive SRP+LASER

therapy or SRP ONLY therapy and then administered local anesthesia (lidocaine with 1:100,000 epinephrine). For the SRP ONLY sites, the involved teeth were thoroughly instrumented using a Cavitron Slimline ultrasonic insert (Dentsply Sirona, Charlotte, N.C.) followed by hand scaling and root planing. The sites were then rinsed and deemed smooth with a pigtail explorer. The gingival tissues were gently compressed using a 2-inch by 2-inch gauze sponge to control bleeding and adapt the marginal gingiva. For the treatment of the SRP+LASER therapy sites, the diode laser was set at 1.5 watts (W) in a pulsed mode (75 hertz) and the fiber tip was conditioned. Following administration of local anesthetic (lidocaine with 1:100,000 epinephrine), treatment was accomplished by placing the tip to the base of the sulcus and moving it circumferentially, removing the inflamed and ulcerated epithelial lining with care not to overheat the treatment area. The fiber tip was cleaned frequently with a moist 2-inch by 2-inch gauze sponge. Following soft tissue curettage, root surfaces were thoroughly instrumented using a slim ultrasonic insert followed by hand scaling and root planing. The sites were then rinsed and deemed smooth with a pigtail explorer. The laser tip was reintroduced to further disinfect the sulcus and to expose the underlying connective tissue to laser energy with the anticipation of further biostimulation. The time element for biostimulation was less than 20 seconds. The interseptal bone was perforated with a periodontal probe to encourage vascularization, and the marginal gingiva was de-epithelialized to a 3 mm zone to delay re-epithelialization of the sulcus. This was to allow more time for healing from the underlying tissues. The gingiva was then compressed with a 2-inch by 2-inch gauze sponge, and the subject was given post-treatment APRIL 2 0 2 1

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TABLE 1

Anthropometric Data # Subjects

# Males

# Females

# Smokers

Age Average

Range

32–80

Average — male

Range — male

32–76

Average — female

Range — female

34–80

Teeth treated # Maxillary

Incisors

Premolars

Molars

# Mandibular

Incisors

Premolars

Molars

instructions that included only light brushing of the treatment sites. Post-treatment pain was expected to be minimal and acetaminophen or ibuprofen was suggested, if needed. The third visit was a one-month post-treatment appointment that included addressing subject concerns, evaluating the healing response and placing emphasis on plaque biofilm control. At the fourth visit (three months post-treatment), CCL, PD and BOP were measured and recorded. This was followed by periodontal maintenance that included scaling and a rubber cup polish. Oral hygiene instructions were reemphasized, especially if the plaque biofilm control was inadequate. The fifth visit (six months posttreatment) and sixth visit (nine months post-treatment) were repeats of the three-month visit. CCL, PD and BOP were measured and recorded and periodontal maintenance and oral hygiene instructions were provided. 254 APRIL

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At the seventh visit (12 to 18 months post-treatment), CCL, PD and BOP were measured and recorded and then the subject was referred for a CBCT scan, a 3D Accuitomo 4 cm x 4 cm, of each treatment site. Subjects were then returned to their dental providers for follow-up care. To maintain calibration, the examinations and measurements at pretreatment and 12 to 18 months post-treatment were performed by the principal examiner (JZ) who was blinded to the provided treatment. All treatment, including laser therapy and scaling and root planing, was accomplished by one investigator (NK). A board-certified oral and maxillofacial radiologist (MR) completed the CBCT analyses and was blinded to the performed treatment. Support services were provided by LH and WL and statistical analyses and interpretation were prepared by DC. Statistical tests included descriptive statistics, independent t-tests comparing treatment groups, repeated measures, three-factorial ANOVA for change in bone height and multiple regression analysis for effects of covariables. The repeated measures approach was used instead of a traditional factorial ANOVA in order to control for the fact that each subject contributed two (potentially related) scores for each variable.

Results

Twenty-seven subjects were examined and five were disqualified due to missed appointments or work schedule conflicts. The results are based on 22 subjects who met all inclusion/exclusion criteria and completed the study protocol. The average age of the 22 subjects (11 male and 11 female) was 57 years (males, 58 years; females, 56 years). The ages ranged from 32 to 80 years (males, 32 to 76 years; females, 34 to 80 years). None was

a current smoker. The anthropometric data is delineated in TA BLE 1 . Every subject had at least one control (SRP ONLY) and one experimental (SRP+LASER) site randomly selected, but several subjects had more than one tooth involved per site area depending on the number of adjacent teeth per site. The treatment sites varied in size from a single tooth up to four adjacent teeth. As a result, 42 teeth were treated as SRP ONLY sites and 64 teeth as SRP+LASER sites. No post-treatment complications such as swelling, bleeding and tooth sensitivity were reported. Minor discomfort was experienced occasionally but no prescription pain medication was necessary. Overall, treatment was well tolerated by all study subjects. Four variables were considered as outcomes. These included CCL, PD, BOP and bone height. BOP was scored dichotomously (yes/no) and the other three variables were measured in millimeters. There were five covariables including age of subject (measured in years), time in treatment (measured in days), arch (maxilla or mandible), tooth surface (mesial or distal) and defect angulation (vertical/infrabony or horizontal). Pretreatment (T1) and post-treatment (T2) scores were used for analysis of outcome variables. Change score was calculated as T2 minus T1 for outcome variables. The five covariables were analyzed as a group for their effect on the various outcomes. After fixing these covariables, treatment was added to the model to see whether it explained any additional variance. This approach identifies factors other than treatment and statistically controls them prior to analysis of the treatment effect. Adding the treatment factor after controlling for covariables showed no effect on three of the outcome variables (CCL, PD and BOP). Treatment did show a significant

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TABLE 2

Verification of Initial Equivalence of SRP ONLY (Control) and SRP+LASER (Experimental) Groups Treatment

SRP ONLY

SRP+LASER

Clinical crown length (mm)

Probing depth (mm)

Bleeding on probing (%)

Bone height (mm)

Mean/Std deviation

7.881/2.024

5.905/0.977

0.833/0.377

4.365/1.832

Mean/Std deviation

7.453/2.027

6.164/1.360

0.813/0.393

4.571/2.110

t-value/p-value

1.064/0.290

1.141/0.256

0.274/0.787

0.529/0.608

Clinical crown length (mm) Probing depth (mm)

Bleeding on probing (%)

Bone height (mm)

Mean/Std deviation

7.345/2.047

3.69/0.765

1.024/0.154

4.203/1.694

Mean/Std deviation

7.016/2.106

3.688/1.056

1.016/0.125

3.932/1.745

t-value/p-value

0.797/0.427

0.016/0.987

0.300/0.765

0.787/0.433

TABLE 3

Comparison Across Treatments at T2 Treatment

SRP ONLY

SRP+LASER

TABLE 4

Change (T2 Minus T1) for SRP ONLY (Control) and SRP+LASER (Experimental) Groups Treatment

SRP ONLY

SRP+LASER

Mean/Std deviation

Clinical crown length (mm)

Probing depth (mm)

Bleeding on probing (%)

Bone height (mm)

–0.536/1.332

–2.214/1.001

–0.810/0.397

–0.162/0.523

Mean/Std deviation

–0.438/1.413

–2.477/1.410

–0.797/0.443

–0.639/0.996

t-value/p-value

0.358/0.721

1.119/0.266

0.153/0.879

3.180/0.002

independent effect on bone height. There were no statistically significant differences in pretreatment variables between the SRP ONLY and SRP+LASER groups as shown in TA BLE 2 . This includes CCL, PD, BOP and interproximal bone height as measured on the pretreatment (T1) CBCT scan. Mean post-treatment (T2) data for both treatment groups are shown in TA BLE 3 , and the mean change in variables from T1 to T2 is depicted in TA BLE 4 . There were no statistically significant differences between the SRP ONLY and SRP+LASER groups for CCL, PD and BOP (p > 0.05); however, there was a significant increase in alveolar bone height for the SRP+LASER (p = 0.002) group when compared to the SRP ONLY group. Direct measurements of the clinical attachment level (CAL) were not part of the study protocol. Because there was no statistically significant difference between the CCL in the treatment

groups, it is reasonable to assume the change in PD is largely due to a gain in clinical attachment. The CAL can be determined indirectly from TA BLE 4 using the change in CCL and the change in PD. The mean bone height for T1 and T2 as it relates to the type of defect is illustrated in TA BLE 5 . For the SRP ONLY group, there were 42 sites total, 33 with horizontal defects and nine with vertical (or infrabony) defects. The SRP+LASER group had 64 total sites: 27 with vertical defects and 37 with horizontal defects. Bone height changes from T1 to T2 for both treatment groups identified by defect morphology are depicted in FIGURE 1 . Repeated measures ANOVA calculations are depicted in TA BLE 6 and demonstrate that vertical defects showed significantly more bone fill (p = 0.003) than horizontal defects. While both treatment groups showed increased bone height from T1 to T2, the degree of bone fill was greater in

the SRP+LASER-treated vertical defects (1.24 mm mean fill) compared to the SRP ONLY sites (0.29 mm mean fill). In comparing horizontal defects, the average gain was 0.1 mm for the SRP ONLY group and 0.22 mm for the SRP+LASER group. The CBCT images (FIGURES 2–5 ) are SRP+LASER treatment examples showing bone height at pretreatment and at post-treatment. While some images demonstrate significant increase in bone height after 12 to 18 months, none of the defects showed complete bone fill.

Discussion

The dental laser has increased public interest in periodontal therapy by avoiding surgical entry, bone manipulation and suturing. Patients want to avoid surgery and post-treatment pain, but does the laser provide the same level of healing and repair as conventional periodontal therapy? APRIL 2 0 2 1

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TABLE 5

Change in Bone Height by Defect Type for SRP ONLY (Control) and SRP+LASER (Experimental) Groups Treatment

Defect types

SRP ONLY

Vertical

Horizontal SRP+LASER

T1 (mm)

T2 (mm)

Mean/Std deviation

6.236/2.313

5.973/ 2.166

Mean/Std deviation

3.855/1.308

3.720/ 1.175

Vertical

Mean/Std deviation

6.021/1.928

4.863/ 1.741

Horizontal

Mean/Std deviation

3.452/1.418

3.213/ 1.388

TABLE 6

Repeated Measures ANOVA Mean squared

F-statistic

p-value

Trials (T1 and T2)

7.772

26.456

0.000

Treatment (TX)

12.063

2.694

0.110

Angulation (ANG)

189.301

40.701

0.000

Trials x TX

2.417

8.226

0.005

Trials x ANG

2.851

9.023

0.003

TX x ANG

0.417

0.090

0.765

FIGURE 1. Bone height changes from T1 to T2 for treatment type and bone angulation.

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Over the past quarter of a century, dental lasers have been the subject of hundreds of studies examining their effects on the dentition, alveolar bone and periodontal hard and soft tissues. These studies are challenged by the multiple laser types, wavelength, current pulsation, exposure time, field of attraction and the variation in delivery of laser energy, all of which can affect clinical outcomes.34–58 A “best-evidence consensus” convened by the American Academy of Periodontology in 2017 had several observations.59 Laser therapy along with conventional scaling and root planing seems to produce modest improvements in CAL, PD and BOP compared to scaling and root planing alone, but there is uncertainty whether these effects were long-term benefits. The consensus is that current evidence is inadequate to conclude that laser therapy provides any additional long-term advantage compared to conventional periodontal treatment. Most diode lasers have a wavelength of 810 nm–960 nm and are limited to soft tissue procedures. The diode laser used in this study has a longer wavelength (1064 nm) that produced deeper soft tissue penetration and greater potential for biostimulation. Asl et al.60 were able to demonstrate increased levels of basic fibroblast growth factor when exposing cells to low-level (810 nm) diode laser irradiation. This would be expected to facilitate repair and possible new periodontal regeneration. Using a 940 nm diode laser, Bozkurt et al.61 irradiated healthy root plates with 0.3 W of diode energy and continuous wave. This induced mineralized nodule formation of cementoblasts, which are important in periodontal repair. The root plates were sections of the cemental surface of previously impacted third molars placed in cell culture inserts.

C D A J O U R N A L , V O L 4 9 , Nº 4

CBCT development allows the clinician to view hard tissue changes following treatment with reasonable accuracy, without exposing the patient to surgical reentry and direct visualization. Its 3D view has brought significant progress in both restorative and endodontic treatment as well as in assessing the scope and dimensions of periodontal pathology. The clinician can view buccal-lingual as well as mesial-distal views all by managing and rotating the existing image. This is a large advantage over observing changes with a twodimensional periapical dental radiograph. This study demonstrated positive results by reducing PD and BOP as well as minimizing changes in CCL for both treatment groups. There was no statistically significant gingival recession for either treatment, which eases concerns about unfavorable aesthetic outcomes. These findings were consistent with our previous findings using an 810 diode laser.1 The statistically significant differences observed in this study were bone height changes, where the SRP+LASER treatment produced gains in bone height compared to SRP ONLY. This was most apparent in vertical, infrabony osseous defects where bone fill is expected to have the greatest potential. These findings suggest that patients with vertical osseous defects may benefit from combining 1064 diode laser therapy with conventional scaling and root planing. Controlled studies such as this study provide the clinician with answers and conclusions and may redirect courses of treatment, but questions are generated that compel future investigations in an attempt to explain why these results occurred. In reference to the graph (FIGURE 1 ) relating bone height changes from T1 to T2, the downward angulation indicates a positive treatment effect and gain in bone support. If this study were

FIGURE S 2 . CBCT bony defect mesial aspect tooth No. 8 at T1, SRP+LASER (2A ). CBCT defect measurement mesial aspect tooth No. 8 at T1, SRP+LASER (2B ). CBCT bony defect mesial aspect tooth No. 8 at T2, SRP+LASER (2C ). CBCT defect measurement mesial aspect tooth No. 8 at T2, SRP+LASER (2D ).

to be extended in time, an additional six months or one year, would there be further improvement in bone levels? An additional unanswered question relates to periodic laser disinfection of the treated sites. Lasers are known to have potent disinfecting properties and biostimulatory properties on dental hard and soft tissues. Will lowlevel laser exposure during recare appointments further enhance pocket reduction and osteogenesis? This could be accomplished at lower energy levels and without conditioning the laser fiber, eliminating the need for local anesthesia and further tissue removal. The realization that dental implants are subject to peri-implant pathology is increasingly apparent. Short-term benefits

such as inflammation control and minor pocket reduction have been observed with nonsurgical laser therapy; however, recommending this modality for longterm treatment has yet to be established. Cosmetic dentistry enjoys increased popularity with bleaching, adult orthodontics and porcelain veneers reaching high levels of acceptance. Treating periodontitis and its bone and soft tissue loss without creating additional gingival recession or other aesthetic issues as well as reducing anesthetic needs and discomfort greatly enhances public acceptance. Does laser therapy give dentistry another treatment option in preventing disease and maintaining periodontal health without creating unfavorable aesthetics? This becomes APRIL 2 0 2 1

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even more important when the clinician is tasked to stabilize a dentition that has extensive reconstructed prostheses.

Conclusions 3A

■

FIGURE S 3 . CBCT bony defect mesial aspect tooth No. 12 at T1, SRP+LASER (3A ). CBCT defect measurement mesial aspect tooth No. 12 at T1, SRP+LASER (3B ). CBCT bony defect mesial aspect tooth No.12 at T2, SRP+LASER (3C ). CBCT defect measurement mesial aspect tooth No. 12 at T2, SRP+LASER (3D ).

FIGURE S 4 . CBCT bony defect distal aspect tooth No. 20 at T1, SRP+LASER (4A ). CBCT defect measurement distal aspect tooth No. 20 at T1, SRP+LASER (4B ). CBCT bony defect distal aspect tooth No. 20 at T2, SRP+LASER (4C ). CBCT defect measurement distal aspect tooth No. 20 at T2, SRP+LASER (4D ).

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Both SRP ONLY and SRP+LASER treatments produced reductions in PD and a marked reduction in BOP. CCL were stable, and minimal gingival recession was observed for both treatment groups. Both treatment groups showed slight improvement in horizontal bone levels from T1 to T2, which was not statistically significant. Infrabony or vertical osseous defects showed significant bone level improvement (p = 0.002) with SRP+LASER compared to the SRP ONLY group. No treatment intervention resulted in complete osseous fill of any infrabony defect within the 12- to 18-month follow-up period. n

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10.1902/jop.2007.070156. 43. Spencer P, Cobb CM, McCollum MH, et al. The effects of CO2 laser and Nd:YAG with and without water/air surface cooling on tooth root structure: Correlation between FTIR spectroscopy and histology. J Periodontol Res 1996 Oct;31(7):453–62. doi: 10.1111/j.1600-0765.1996. tb01409.x. 44. Gopin BW, Cobb CM, Rapley JW, et al. Histologic evaluation of soft tissue attachment to CO2 laser-treated root surfaces: an in vivo study. Int J Periodontics Restorative Dent 1997;17(4):316–325. 45. Nikolopoulos S, Naoumidou I, Nikolopoulou M, et al. ArF-193 excimer laser and Emdogain in the treatment of experimental periodontitis: An experimental study in rabbits. Photomed Laser Surg 2004 Aug;22(4):357–62. doi: 10.1089/pho.2004.22.357. 46. Theodoro LH, Sampaio JE, Haypek P, et al. Garcia VG. Effect of Er:YAG and diode lasers on the adhesion of blood components and on the morphology of irradiated root surfaces. J Periodontol Res 2006 Oct;41(5):381–90. doi: 10.1111/j.1600-0765.2005.00846.x. 47. Assaf M, Yilmaz S, Kuru B, et al. Effect of the diode laser on bacteremia associated with dental ultrasonic scaling: A clinical and microbiological study. Photomed Laser Surg 2007 Aug;25(4):250–6. doi: 10.1089/ pho.2006.2067. 48. Trylovich DJ, Cobb CM, Pippin DJ, et al. The effects of the Nd:YAG laser on in vitro fibroblast attachment to endotoxin-treated root surfaces. J Periodontol 1992 Jul;63(7):626–32. doi: 10.1902/jop.1992.63.7.626. 49. Friesen LR, Cobb CM, Rapley JW, et al. Laser irradiation of bone: II. Healing response following treatment by CO2 and Nd:YAG lasers. J Periodontol 1999 Jan;70(1):75–83. doi: 10.1902/jop.1999.70.1.75. 50. McDavid VG, Cobb CM, Rapley JW, et al. Laser irradiation of bone: III. Long-term healing following treatment by CO2 and Nd:YAG lasers. J Periodontol 2001 Feb;72(2):174–82. doi: 10.1902/jop.2001.72.2.174. 51. Gutknecht N, Franzen R, Schippers M, et al. Bactericidal effect of 980-nm diode laser in the root canal wall dentin of bovine teeth. J Clin Laser Med Surg 2004 Feb;22(1):9–13. doi: 10.1089/104454704773660912. 52. Pant V, Dixit J, Agrawal AK, et al. Behavior of human periodontal ligament cells on CO2 laser irradiated dentinal root surfaces: An in vitro study. J Periodontol Res 2004 Dec;39(6):373–9. doi: 10.1111/j.16000765.2004.00751.x. 53. Qin YL, Luan XL, Bi LJ, et al. Comparison of toluidine blue-mediated for periodontitis in rats. J Periodontal Res 2008 Apr;43(2):162–7. doi: 10.1111/j.16000765.2007.01007.x. 54. de Mendonça AC, Máximo MB, Rodrigues JA, et al. Er:YAG Laser, ultrasonic system and curette produce different profiles on dentine root surfaces: An in vitro study. Photomed Laser Surg 2008 Apr;26(2):91–7. doi: 10.1089/pho.2007.2129. 55. de Almeida JM, Theodoro LH, Bosco AF, et al. In vivo effect of photodynamic therapy on periodontal bone loss in dental furcations. J Periodontol 2008 Jun;79(6):1081–8. doi: 10.1902/jop.2008.070456. 56. Lopes BM, Marcantonio RA, Thompson GM, et al. Short-term clinical and immunologic effects of sealing and root planing with Er:YAG laser in chronic periodontitis.

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J Periodontol 2008 Jul;79(7):1158–67. doi: 10.1902/ jop.2008.070600. 57. Mummolo S, Marchetti E, Di Martino S, et al. Aggressive periodontitis: Laser Nd:YAG treatment versus conventional surgical therapy. Eur J Paediatr Dent 2008 Jun;9(2):88–92. 58. Kara C, Demir T, Orbak R, et al. Effect of Nd:YAG laser irradiation on the treatment of oral malodour associated with chronic periodontitis. Int Dent J 2008 Jun;58(3):151–8. doi: 10.1111/j.1875-595x.2008.tb00191.x. 59. Mills MP, Rosen PS, Chambrone L, et al. American Academy of Periodontology best evidence consensus statement on the efficacy of laser therapy used alone or as an adjunct to nonsurgical and surgical treatment of periodontitis and peri-implant diseases. J Periodontol 2018 Jul;89(7):737–742. doi: 10.1002/JPER.17-0356. 60. Asl RM, Ghoraeian P, Monzavi A, et al. Analysis of gene expression of basic fibroblast growth factor (bFGF) following photodynamic therapy in human gingival fibroblasts. Photodiagnosis Photodyn Ther 2017 Dec;20:144–147. doi: 10.1016/j.pdpdt.2017.09.010. Epub 2017 Sep 19. 61. Bozkurt SB, Hakki EE, Kayis SA, et al. Biostimulation

with diode laser positively regulates cementoblast functions, in vitro. Lasers Med Sci 2017 May;32(4):911–919. doi: 10.1007/s10103-017-2192-z. Epub 2017 Mar 22. T HE CORRE S P ON DIN G AU T HOR , Lisa Harpenau, DDS, MS, MBA, MA, can be reached at Lharpenau@pacific.edu.

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pharmacological reactions C D A J O U R N A L , V O L 4 9 , Nº 4

Top 10 Prescribed Drugs: What Do Dental Clinicians Need To Know Matthew Choi, BS, and Aviv Ouanounou, BSc, MSc, DDS

abstract Background: Current demographic data clearly show that the world population is aging, and projections suggest that the percentage of older people will increase. This part of the population is known to take many prescribed and nonprescribed medications. This paper aims to summarize important pharmacological reactions of the top 10 most prescribed drugs in 2018 and dental treatment. Types of studies reviewed: A search was conducted for relevant articles by using a strategy of crossing the top 10 most prescribed drugs in 2018 AND the words (dental treatment) OR (dentistry) OR (dental). Results: The authors reviewed the top 10 most commonly prescribed drugs in the U.S. during 2018 and their relevant interactions with dental treatment, local anesthetic and other prescribed drugs. This paper summarizes these relevant interactions, presentations and clinical implications of these interactions to educate dentists on the consequences of such interactions. Practical implications: This paper aims to improve awareness of understanding of important interactions with drugs and dental treatment so that dentists can properly manage and prevent such occurrences. Key words: Drug; dentistry, dental treatment, local anesthetic, pharmacological, interactions

AUTHORS Matthew Choi, BS, is a fourth-year dental student at the faculty of dentistry at the University of Toronto. Conflict of Interest Disclosure: None reported.

Aviv Ouanounou, BSc, MSc, DDS, is an assistant professor in the department of clinical sciences (pharmacology and preventive dentistry) at the faculty of dentistry at the University of Toronto. He is a fellow of the International College of Dentistry, the American College of Dentistry and the Pierre Fauchard Academy. Conflict of Interest Disclosure: None reported.

ith a growing proportion of elderly patients, dentists will begin to see more and more patients on multiple pharmacotherapeutic regimens for their various disease. Far too often, patients and even some dentists forget that the oral cavity is a vital part of overall health and consequences of these prescribed drugs are often unaccounted for. The oral cavity is a conduit for the rest of patient health. Oftentimes in

dental offices, patients are made aware of systemic conditions that they may not have known about. It is imperative that the dentist be made aware of the potential interactions between these drugs and the health care services dentists may provide as oral health professionals. Failure to account for these potential interactions can not only complicate dental care but also endanger patient health. An example of this may be the prescription of an azole antifungal agent for a patient on warfarin, which could lead APRIL 2 0 2 1

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to suppression of warfarin metabolizing enzymes, ultimately causing dangerous adverse effects as a result of increased systemic levels of warfarin resulting in an increased risk of bleeding complications. To help dental professionals make informed decisions with regard to treatment for their patients, the authors reviewed the 10 most commonly prescribed drugs. The top 10 most commonly prescribed drugs for 2018 as reported by the IQVIA Institute for Human Data Science are atorvastatin, lisinopril, levothyroxine, amlodipine, hydrocodone-acetaminophen, gabapentin, omeprazole, metformin, amoxicillin and losartan.1 The pharmacology of each drug is discussed as well as the potential and reported interactions that these pharmacological agents will have with dental treatment. Other aspects of dental treatment that were considered include dental treatment itself, local anesthetic preparations and their components and drugs prescribed by dentists. Negligence to these potential interactions may not only complicate the treatment provided by dentists, but also potentially place patients in critical danger and even death. It is imperative that dentists recognize these potential interactions and adjust accordingly to provide optimal and personalized dental treatment. The authors reviewed the 10 most commonly prescribed drugs during 2018 in the U.S. and their potential interactions with dental treatment, local anesthetic preparations and their components as well as other drugs dentists may prescribe (TA BLE ).1

Atorvastatin (Lipitor) Background

Atorvastatin (Lipitor) belongs to the HMG-CoA reductase inhibitor class of drugs aimed at reducing cholesterol levels and thus reducing the incidence of cerebrovascular and 262 APRIL

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cardiovascular events such as angina, myocardial infarction and stroke.2

Pharmacology

Atorvastatin reduces cholesterol levels by inhibiting the 3-hydroxy-3-methylglutaryl-coenzyme A reductase enzymes and is essential for the production of cholesterol.2–4 Cholesterol, like other fats, is transported and distributed by lipoprotein complexes.5 Atorvastatin targets these lipoprotein complexes by lowering the amounts of low-density lipoproteins, triglycerides and overall cholesterol

It is imperative that dentists recognize these potential interactions and adjust accordingly to provide optimal and personalized dental treatment.

banks, there seem to be little interactions that would interfere or complicate inperson dental treatment or administration of local anesthetic. However, there are potential drug interactions between CYP3A4 modifiers that dentists may prescribe, such as clarithromycin, and should thus be considered before prescribing.7 Warfarin also increases international normalized ratio (INR) when used concurrently with statins, and thus dentists should be prepared for increased bleeding if the INR values are not within normal limits.8

Lisinopril (Zestril, Prinivil) Background

Lisinopril (Zestril, Prinivil) is the second most prescribed drug and belongs to the class of angiotensin I-converting enzyme (ACE) inhibitors.9–11 This works by inactivating a step along the renin-angiotensin-aldosterone-system (RAAS) to help control blood pressure and other cardiovascular disease.

Pharmacology

levels while increasing high-density lipoproteins,5 thereby limiting the amount of cholesterol and lipids that are available for initiating the atherosclerosis process.5 Atorvastatin, like other statins, is primarily metabolized by the cytochrome P450 3A4 (CYP4A4) enzymes, and thus drug interactions can arise between inducers and inhibitors of this enzyme. Patients may also exhibit variable pharmacodynamics of the drug depending on the patient’s metabolic genotype.6 Statins can also elevate specific liver enzymes, and thus proper liver functioning should be monitored.

The RAAS pathway is a complex, multiorgan physiological response aimed at maintaining blood pressure and volume in the body. This pathway starts when the kidneys and other tissues release renin, which is then cleaved into angiotensin I.9,12–14 Angiotensin I is then activated by angiotensin I-converting enzyme, found in the lungs and kidneys, into angiotensin II.14 Angiotensin II works on various receptors to increase blood pressure and blood volume.14 Centrally, it acts on receptors to increase aldosterone release to increase sodium retention while acting peripherally to increase vascular tone.14

Interactions

Interactions With Dental Treatment

From conducting searches of the literature and examining drug information in pharmaceutical drug

Drug interactions with lisinopril are bound to occur as the proportion of people being diagnosed with

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TABLE

Top 10 Most Prescribed Drugs in the United States and Potential Interactions With Dental Treatment Drug

hypertension increases and as they seek pharmaceutical management of their condition. While the drug is predominantly safe to use, it does present the possibility of interacting with some aspects of dental care. Specifically, nonsteroidal antiinflammatory drugs (NSAIDs) and ACE inhibitors may interact and cause antihypertensive effects.15,16 Furthermore, they have also been linked to increased risk of acute kidney injury especially in volume-depleted patients.16 ACE inhibitors can also cause various and relevant dental side effects such as rash, dry cough, loss of taste and taste changes, xerostomia, ulceration, burning mouth, neutropenia, etc.16 The use of ACE inhibitors such as lisinopril can manifest into a rare, but lethal side effect known as angioedema.16,17 While more serious presentations may involve severe facial swelling and redness, other more subtle signs may include isolated or marginal swelling in the tongue and mouth.16,17 Patients presenting with angioedema should be referred to the local emergency department for immediate medical attention.

Levothyroxine (Synthroid, Levoxyl, Levothroid, Unithroid) Background

Levothyroxine (Synthroid, Levoxyl, Levothroid, Unithroid) is the third most prescribed drug in the U.S. and is a hormone replacement therapy for patients with hypothyroidism.

Pharmacology

The thyroid gland produces two types of thyroid hormone: T4 and T3.18–20 It predominantly produces T4 that circulates around the body and is deiodinated into T3, which is more potent, by targeting tissues and organs when needed.18–20 Levothyroxine mimics

Potential interactions

Atorvastatin (Lipitor)

• Altered metabolism by CYP3A4 modulators (clarithromycin) • Increased INR when used with warfarin and potential of bleeding • Periodontal therapy adjunct

Lisinopril (Zestril, Prinivil)

• Hypotension when used with other antihypertension drugs • MSAIDS may interact and cause reduction in the antihypertensive effect • Rash, dry cough, dysgeusia, xerostomia, ulcerations, burning mouth, neutropenia

Levothyroxine (Synthroid, Levoxyl, Levothyroid, Unithroid)

• No interactions but be wary for signs of hyperthyroidism and hypothyroidism

Amlodipine (Norvasc)

• Gingival enlargement, xerostomia, dysgeusia • Hypotension when used with benzodiazepines and macrolides

Acetaminophen and Hydrocodone (Norco, Vicodin, Lorcet)

• Hepatic impairment • Review prescribed and over-the-counter medications for acetaminophen • Hyperalgesia, respiratory depression, loss of consciousness and hypotension

Gabapentin (Neurontin)

• Synergistic depressive effects with opioids

Omeprazole (Prilosec) and Lansoprazole (Prevacid)

• Altered metabolism by CYP3A4 and CYP2C19 modulators • Increased INR and prothrombin time when used with warfarin and increased risk of bleeding • Increased bioavailability of clarithromycin when used concurrently

Metformin (Glucophage)

• Dysgeusia • Caution for hypoglycemic states • Periodontal therapy adjunct

Amoxicillin (Amoxil)

• Hypersensitivity reactions

Losartan (Cozaar and Hyzaar)

• Synergistic effects with other antihypertensives • Xerostomia, angioedema, sinusitis, dysgeusia, cough and orthostatic hypotension

this by acting as a T4 supplement, thus minimizing the chance of thyrotoxicosis.

Interactions With Dental Treatment

Patients who are diagnosed with hypothyroidism may have problems with hemostasis as well as an increased risk of infection.21 These patients may also be susceptible to cardiovascular disease such as arteriosclerosis and dyslipidemia.21 Dentists should be aware of these potential presentations, as the patient may be taking other drugs to manage those conditions if hypothyroidism is not managed properly. Patients whose hypothyroidism is well managed generally do not present any contraindications to care, as the body’s metabolism of the thyroid hormone is tightly bound and controlled.18–20

Amlodipine (Norvasc) Background

Amlodipine (Norvasc) is an oral dihydropyridine calcium channel blocker and is approved for the management and treatment of hypertension and coronary artery disease.22 It has other off-label uses for diabetic nephropathy, left ventricular hypertrophy, Raynaud phenomenon and silent myocardial ischemia.22,23

Pharmacology

Amlodipine works as a dihydropyridine calcium antagonist that prevents the transmembrane influx of calcium ions into vascular smooth and cardiac muscle. Data has shown that it binds to both dihydropyridine and nondihydropyridine sites.22,23 Inhibiting the influx of calcium inhibits the contractile action of these APRIL 2 0 2 1

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muscles.22,23 Amlodipine appears to have a greater effect on vascular smooth muscle than cardiac muscle, which allows for management of hypertension by decreasing peripheral resistance without reducing cardiac output,22,23 thus reducing the myocardial oxygen demand and sparing the heart.

Interactions With Dental Treatment

In rare cases, amlodipine has been reported to cause drug-induced gingival enlargement.16,24 The reasons for this are not entirely known but have been linked to certain predisposing factors, such as poor oral hygiene.16,24 Among calcium channel blocker type drugs, the incidence of gingival hyperplasia with amlodipine is less than others, but has been reported in rare cases.24 In such cases where drug substitution is not appropriate, treatment consists of surgical debridement of the area and surgical removal of the enlarged tissue. Other relevant dental side effects include dry mouth and altered taste.16 Drug interactions specific to calcium channel blockers include benzodiazepines, erythromycins and clarithromycin.16 Concomitant use of macrolide antibiotics and calcium channel blockers has shown to increase the risk of hypotension and shock, particularly in older patients.25,26

Hydrocodone-Acetaminophen (Norco, Vicodin, Lorcet) Background

Hydrocodone-acetaminophen (Norco, Vicodin, Lorcet) is used for pain relief, allowing for a more profound sense of analgesia with the use of opioids to target central mechanisms when NSAIDs are insufficient.27 The combination is typically used for moderate to severe pain control in postoperative patients, trauma and cancer.27 264 APRIL

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Pharmacology

Acetaminophen Mechanism Acetaminophen’s mechanism of action is complex and does not provide a clear and concise answer for its analgesic effects.28,29 The mechanism of action is believed to be a result of cyclooxygenase-2 inhibition leading to decreased synthesis of prostaglandins with antipyretic and analgesic properties.29 However, it has not been shown to have antiinflammatory properties like NSAIDs.29 Acetaminophen is metabolized in the liver into acetaminophen glucuronide,

Patients with chronic opioid usage have been reported to experience tolerance to opioids and hyperalgesia.

acetaminophen sulfate and N-acetyl-pbenzoquinone imine (NAPQI).29 NAPQI is toxic but is inactivated by binding to glutathione sulfhydryl groups and is then excreted.29 Patients with decreased liver function may lead to impaired metabolism of acetaminophen and cause acetaminophen-induced hepatotoxicity.30 Opioid Mechanism Opioids like hydrocodone work as agonists of mu-opioid receptors and, to some extent, delta receptors.31 Activation of these receptors leads to inhibition of G-proteins and the closing of voltage-sensitive calcium channels, stimulation of K+ efflux leading to hyperpolarization and reduced adenosine monophosphate production with the overall effect of reduction neuronal

excitability and nociceptive impulse transmission.31 Opioids are metabolized in the liver to active and inactive compounds.32 In the case of hydrocodone, it is metabolized by cytochrome P450 enzymes into hydromorphone, an active metabolite that is four to six times more potent than hydrocodone.32

Interactions With Dental Treatment

Acetaminophen and hydrocodone do not generally pose any significant hurdle to dentists providing dental treatment to patients. However, dentists must be aware of patients with chronic opioid use and hepatic impairment when prescribing this or treating patients using this drug. Patients with hepatic impairment are at an increased risk of acetaminophen-induced hepatoxicity. Chronic Opioid Usage Patients with chronic opioid usage have been reported to experience tolerance to opioids and hyperalgesia. Several studies have shown that patients with chronic opioid usage report lower thresholds of pain and increased responses to cold stimuli compared to controls.33–36 The mechanism of opioid-induced hyperalgesia is not yet understood, but there is speculation that it is due to neuroplastic changes occurring peripherally and centrally that lead to sensitization of nociceptive pathways, among other theories.37 Thus, dentists should be wary of these changes and aware that patients may require higher doses of analgesics or even sedation during more painful and lengthy procedures. Hepatic Problems Acetaminophen-induced hepatoxicity is the most common cause of acute liver failure in the U.S. and the U.K.30 Acetaminophen has a narrow window of therapeutic efficacy and should be

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prescribed with caution, especially in patients with suspected or confirmed liver disease.30 Dentists prescribing acetaminophen for patients with hepatic deficiencies should consult with the patient’s physician prior to administering acetaminophen.30 Acetaminophen is one of the most commonly purchased over-the-counter medications and is available in many formulations other than those for pain. Patients may be unaware they are taking multiple products that contain acetaminophen, thereby increasing the risk of toxicity. Overdosage of acetaminophen through the accumulation of acetaminophen by various methods represents one of the most common ways for acetaminopheninduced hepatotoxicity. Dentists should be aware of this potential and review all prescribed and over-thecounter medications with patients prior to prescribing hydrocodoneacetaminophen combinations.

Gabapentin (Neurontin) Background

Gabapentin (Neurontin) is marketed as an anticonvulsant drug that mimics the gamma aminobutyric acid (GABA) neurotransmitter.38 It is also now used as part of chronic pain management regimens such as chronic pain, neuralgia and restless legs syndrome.

Pharmacology

Gabapentin is prescribed as an analgesic and anticonvulsant, but the exact mechanism is unclear.38,39 Gabapentin is believed to work because of its structural similarities to GABA, however there is no clear effect of gabapentin on GABA binding, uptake or degradation.38,39 Some studies have shown that gabapentin binds to certain subunits of the voltage-gated calcium channels, but the exact mechanism is still unknown.38,39

Interactions With Dental Treatment

Conducting a search of the literature did not report any notable interactions with dental treatment, and other sources in the literature have largely reported this as a safe analgesic and anticonvulsant drug despite the exact mechanism of action being unknown. However, dentists should be wary of potentially synergistic effects between gabapentin and opioids if prescribed for pain relief for patients. These two classes of drugs may

Acetaminophen is one of the most commonly purchased over-the-counter medications and is available in many formulations other than those for pain. potentiate their effect and necessitate lowering dosages of opioids if a patient reports taking gabapentin.40

Omeprazole (Prilosec) Background

Omeprazole (Prilosec) belongs to the group of pharmacological agents called proton pump inhibitors (PPI) and is used for the treatment of various gastrointestinal disorders, notably peptic ulcer disease, gastroesophageal reflux disease and H. pylori infections. Omeprazole works by inhibiting H+/K+–ATPase pumps in parietal cells and thus halting the final step in acid secretion.41

Pharmacology

Omeprazole belongs to a new class of antisecretory compounds, a group

which suppresses gastric acid secretion by specifically inhibiting H+, K+–ATPase and do not possess anticholinergic or H2 histamine antagonistic properties.41,42 The drug is highly protein bound and is rapidly distributed in plasma.41,42 Omeprazole can only inhibit active pumps and is best administered with the first meal of the day after an overnight fast.

Interactions With Dental Treatment

Omeprazole is metabolized by cytochrome P450 isozymes CYP2C19 and CYP3A4 and has shown to interact heavily with CYP2C19.41,42 Research reports that omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, all of which are metabolized in the liver. Concomitant use of omeprazole and warfarin can increase INR and prothrombin time and, in the dental setting, can lead to poor hemostasis and hemorrhagic complications. Patients taking both drugs concomitantly should be monitored for increases in INR. Omeprazole has also been shown to increase the bioavailability of clarithromycin, and dentists should be aware of this if prescribing clarithromycin.43

Metformin (Glucophage) Background

Metformin (Glucophage) is the most commonly prescribed oral hypoglycemic drug for its improvement in glucose metabolism and diabetes-related complications.44 Metformin’s mechanism of action is not entirely understood, but it is believed to have multiple modes of action.44

Pharmacology

Metformin’s primary use is to treat diabetes mellitus and its associated complications.44 The drug’s mechanism of action is largely unknown, but recent advances have shown that it may also be useful in treating cancers, such as prostate, breast and lung, due to its ability APRIL 2 0 2 1

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to target differences in cell metabolism between normal and abnormal cells. The main mechanism by which metformin works is through inhibition of hepatic gluconeogenesis and opposing the action of glucagon.44 It also decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.44 Metformin’s advantage over sulfonylureas is that it does not cause hypoglycemia or hyperinsulinemia.45

Interactions With Dental Treatment

Metformin is a generally well-tolerated medication for dental treatment and does not pose any significant interactions with dental treatment. A systematic review of online articles did not yield any results where metformin interacted negatively with drugs or treatment prescribed by dentists. However, dentists should be wary of the potential of poorly managed diabetic patients on multiple drug therapies. Improper management may lead to hypoglycemic states, and dentists should have adequate provisions and emergency procedures and training to tackle such events. Although a search of the literature yielded no significant interactions with dental treatment, there was ample research supporting the local application of metformin as an adjunct for the treatment of periodontal disease. Pradeep et al. reported on various occasions that the local application of metformin into the periodontal pocket achieved statistically significant reductions in probing depth and gains in clinical attachment level when used in combination with scaling and root planing.46,47

Amoxicillin (Amoxil) Background

Amoxicillin (Amoxil) is one of the most commonly used antibiotics due to 266 APRIL

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its broad spectrum of activity and uses against many types of infections and bacteria, and covers mainly gram positive and some gram negative bacteria in various infections.48–50 It is a penicillin antibiotic that has been modified with the hydroxylation of the phenyl side chain to combat antibiotic resistance.51

Pharmacology

Amoxicillin belongs to the class of antibiotics known as beta-lactams due to their main active functional group known as a beta-lactam ring and

Metformin is a generally well-tolerated medication for dental treatment and does not pose any significant interactions with dental treatment. are also classified as bactericidal.50 It exerts a bactericidal effect by binding to penicillin-binding proteins to inhibit the transpeptidation process as the cells grow and divide.50 This leads to lysis of the bacterial cell wall and destruction of the cell. Bacteria have developed resistance to this type of antibiotic and so researchers have added an amino group onto the penicillin to combat resistance mechanisms, such as beta-lactamase.

Interactions With Dental Treatment

Amoxicillin for the most part does not interact negatively with dental treatments such as scaling and root planing, caries management and endodontic or periodontal therapy. It also does not interact negatively with local anesthetics or epinephrine.

Dentists should be wary of patients who are allergic to penicillin-group drugs, as the resulting hypersensitivity reactions may be fatal. The three most common adverse events of amoxicillin usage involve skin, the gastrointestinal system and the liver and biliary system.50,52 One study found that penicillin-group drugs were associated with increased risk of bleeding in patients who were administered warfarin for long periods of time.53 However, a randomized control trial found that the amoxicillin-clavulanic acid combination did not negatively affect INR values.54 The proposed mechanism for increased risk of bleeding is due to the belief that antibiotics like amoxicillin may alter vitamin K-producing gut microbes, which would then increase INR values.55 Dentists should be aware of this potential reaction and consult with the patient’s physician about their INR values before proceeding with procedures that pose the risk for increased bleeding.

Losartan (Cozaar, Hyzaar) Background

Losartan (Cozaar, Hyzaar) is an angiotensin II receptor antagonist used for the management of patients with hypertension and heart failure.56,57 It is a much more selective mechanism of action compared to drugs like beta blockers and is highly effective, with about one-third of severe hypertension patients responding to this drug. From a patient perspective, it has good efficacy, a favorable tolerability profile and an easyto-follow dosing regimen of once daily.56,57

Pharmacology

Angiotensin II is the product of the reaction catalyzed by ACE, which produces profound and potent vasoconstriction in RAAS and is critical in regulating blood pressure.14 Losartan works by specifically inhibiting the

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AT1 receptor commonly found in many tissues.56 The drug is further metabolized into an active metabolite, which helps it sustain its antihypertensive effects and allows for a simple dosing regimen.58 Losartan is metabolized by cytochrome P450 isozymes CYP2C9 and CYP2A4 into active metabolites.58,59 The majority of losartan and its metabolites are eliminated through renal and biliary excretion, with the latter making up the bulk of its elimination.59

Interactions With Dental Treatment

Angiotensin II receptor blockers, like other antihypertensive drugs, can interact with a variety of drugs that are crucial to dental treatment.16 Some of the more specific interactions include systemic antifungals and sedatives that may be used in some situations in clinical practice.16 Relevant dental side effects include xerostomia, angioedema, sinusitis, taste loss and cough.16 Similar to ACE inhibitors, angiotensin receptor II blockers can interact negatively with NSAIDs and exacerbate antihypertensive effects and cause acute kidney injury, particularly in volume-depleted patients. One research study of 22 hypertensive patients found that patients with untreated hypertension were more likely to exhibit a reduced perception to painful stimuli compared to normotensives.60 When prescribed antihypertensive medications like losartan, their perception of pain increased, which the researchers could not attribute to the reduction in blood pressure.60 They speculated that there may be specific pharmacodynamic interactions between the angiotensin II AT1 receptors and nociceptors that are responsible for this altered pain perception.59

Conclusion

This paper highlights the idea that dentists are not just responsible for teeth,

but the oral cavity and patient health as a whole. With an aging population, it is only natural to expect that more and more people will be diagnosed with chronic systemic conditions that will need to be managed pharmacologically. While dental care is focused on the oral cavity, its consequences and effects can be far reaching and have the potential to affect a patient’s overall health. Dentists must be aware of these potential consequences to mitigate the level of risk that their patients will be exposed to. By being aware of these potential interactions, dentists can minimize patient risk, improve treatment outcomes and create a better overall experience for both patients and the dentist. n RE FE RE N C E S 1. Medicine Use and Spending in the U.S. — A Review of 2018 and Outlook to 2023. www.iqvia.com/insights/the-iqviainstitute/reports/medicine-use-and-spending-in-the-us-a-reviewof-2018-and-outlook-to-2023. Accessed May 2019. 2. Fentoglu O, Sozen T, Oz SG, Kale B, Sonmez Y, Tonguc MO, et al. Short-term effects of periodontal therapy as an adjunct to antilipemic treatment. Oral Dis 2010 Oct;16(7):648–54. doi: 10.1111/j.16010825.2010.01668.x. 3. Bertl K, Parllaku A, Pandis N, Buhlin K, Klinge B, Stavropoulos A. The effect of local and systemic statin use as an adjunct to nonsurgical and surgical periodontal therapy — a systematic review and meta-analysis. J Dent 2017 Dec;67:18– 28. doi: 10.1016/j.jdent.2017.08.011. 4. Bertl K, Steiner I, Pandis N, Buhlin K, Klinge B, Stavropoulos A. Statins in nonsurgical and surgical periodontal therapy. A systematic review and meta-analysis of preclinical in vivo trials. J Periodontal Res 2018 Jun;53(3):267–287. doi: 10.1111/ jre.12514. Epub 2017 Dec 6. 5. Rohrl C, Stangl H. Cholesterol metabolism-physiological regulation and pathophysiological deregulation by the endoplasmic reticulum. Wien Med Wochenschr 2018 Sep;168(11–12):280–285. doi: 10.1007/s10354-0180626-2. Epub 2018 Feb 27. 6. Zhang T. Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for atorvastatin and its metabolites. Eur J Pharm Sci 2015 Sep 18;77:216–29. doi: 10.1016/j.ejps.2015.06.019. Epub 2015 Jun 24. 7. Amsden GW, Kuye O, Wei G. A study of the interaction potential of azithromycin and clarithromycin with atorvastatin in healthy volunteers. J Clin Pharmacol 2002 Apr;42(4):444–9. 8. Andrus MR. Oral anticoagulant drug interactions with statins: Case report of fluvastatin and review of the literature. Pharmacotherapy 2004 Feb;24(2):285–90. doi: 10.1592/ phco.24.2.285.33137. 9. Lisinopril. www.accessdata.fda.gov/drugsatfda_docs/

label/2009/019777s054lbl.pdf. Accessed Aug. 14, 2019. 10. Olvera Lopez E, Parmar M, Pendela VS, Terrell JM. Lisinopril. Treasure Island, Fla.: StatPearls Publishing; 2019. www.ncbi.nlm.nih.gov/books/NBK482230/. 11. Gomez HJ, Cirillo VJ, Moncloa, F. The clinical pharmacology of lisinopril. J Cardiovasc Pharmacol 1987;9 Suppl 3:S27–34. doi: 10.1097/00005344-19870000300008. 12. Ruster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol 2006 Nov;17(11):2985–91. doi: 10.1681/ASN.2006040356. Epub 2006 Oct 11. 13. Koh KK, Quon MJ. Targeting converging therapeutic pathways to overcome hypertension. Int J Cardiol 2009 Mar;132(3):297–9. doi: 10.1016/j.ijcard.2008.11.150. 14. Fountain JH, Lappin SL. Physiology, Renin Angiotensin System. Treasure Island, Fla.: StatPearls Publishing; 2019. www. ncbi.nlm.nih.gov/books/NBK470410. 15. Pavličević I, Kuzmanić M, Rumboldt M, Rumboldt Z. Interaction between antihypertensives and NSAIDs in primary care: A controlled trial. J Popul Ther Clin Pharmacol 2008;15(3):372–82. 16. Southerland JH, Gill DG, Gangula PR, Halpern LR, Cardona CY, Mouton CP. Dental management in patients with hypertension: Challenges and solutions. Clin Cosmet Investig Dent 2016;8:111–20. doi: 10.2147/CCIDE.S99446. 17. Kaufman MB. ACE inhibitor — related angioedema. Pharmacovigilance forum. P T 2013 Mar;38(3):170–172. 18. Visser TJ. Pathways of thyroid hormone metabolism. Acta Medica Austriaca 1996;23(1–2):10–6. 19. Bianco AC, Kim BW. Deiodinases: Implications of the local control of thyroid hormone action. J Clin Invest 2006 Oct;116(10):2571–9. doi: 10.1172/JCI29812. 20. Mullur R, Liu YY, Brent G. Thyroid hormone regulation of metabolism. Physiol Rev 2014 Apr;94(2):355–82. doi: 10.1152/physrev.00030.2013. 21. Chandna S, Bathla M. Oral manifestations of thyroid disorders and its management. Indian J Endocrinol Metab 2011 Jul;15(Suppl 2):S113–6. doi: 10.4103/22308210.83343. 22. Amlodipine. Accessed Aug. 16, 2019. www.accessdata. fda.gov/drugsatfda_docs/label/2005/019787s038lbl.pdf. 23. Bulsara KG, Cassangol M. Amlodipine. Treasure Island, Fla.: StatPearls Publishing; 2019. www.ncbi.nlm.nih.gov/ books/NBK519508. 24. Madi M, Shetty SR, Babu SG, Achalli S. Amlodipineinduced gingival hyperplasia — a case report and review. West Indian Med J 2015 Jun;64(3):279–82. doi: 10.7727/ wimj.2014.089. Epub 2015 Apr 14. 25. Gandhi S, Fleet JL, Bailey DG, McArthur E, Wald R, Rehman F, et al. Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury. JAMA 2013 Dec 18;310(23):2544–53. doi: 10.1001/jama.2013.282426. 26. Wright AJ, Gomes T, Mamdani MM, Horn JR, Juurlink DN. The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers. CMAJ 2011 Feb 22;183(3):303–7. doi: 10.1503/cmaj.100702. Epub 2011 Jan 17. 27. Habibi M, Kim PY. Hydrocodone and Acetaminophen Treasure Island, Fla.: StatPearls Publishing; 2019. www.ncbi. nlm.nih.gov/books/NBK538530. 28. Graham GG, K.F. S. Mechanism of action of APRIL 2 0 2 1

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paracetamol. Am J Ther Jan–Feb 2005;12(1):46–55. doi: 10.1097/00045391-200501000-00008. 29. Jozwiak-Bebenista M, Nowak JZ. Paracetamol: Mechanism of action, applications and safety concern. Acta Pol Pharm 2014 Jan–Feb;71(1):11–23. 30. Lee WM. Acetaminophen (APAP) hepatotoxicity — Isn’t it time for APAP to go away? J Hepatol 2017 Dec;67(6):1324– 1331. doi: 10.1016/j.jhep.2017.07.005. Epub 2017 Jul 20. 31. Trivedi M, Shaikh S, Gwinnut C. Pharmacology of Opioids. Update in Anaesth 2008 Feb;118–24. 32. Barakat NH, Atayee RS, Best BM, Pesce AJ. Relationship between the concentration of hydrocodone and its conversion to hydromorphone in chronic pain patients using urinary excretion data. J Anal Toxicol 2012 May;36(4):257–64. doi: 10.1093/jat/bks019. 33. Araldi D, Ferrari LF, Levine JD. Hyperalgesic priming (type II) induced by repeated opioid exposure: Maintenance mechanisms. Pain 2017 Jul;158(7):1204–1216. doi: 10.1097/j.pain.0000000000000898. 34. Hooten WM, Lamer TJ, Twyner C. Opioid-induced hyperalgesia in community-dwelling adults with chronic pain. Pain 2015 Jun;156(6):1145–52. doi: 10.1097/j. pain.0000000000000170. 35. Hay JL, White JM, Bochner F, Somogyi AA, Semple TJ, Rounsefell B. Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. J Pain 2009 Mar;10(3):316– 22. doi: 10.1016/j.jpain.2008.10.003. Epub 2008 Dec 19. 36. Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: A preliminary prospective study. J Pain 2006 Jan;7(1):43–8. doi: 10.1016/j.jpain.2005.08.001. 37. Lee M, Silverman S, Hansen H, Patel V, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician Mar–Apr 2011;14(2):145–61. 38. Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol 2006 Feb;6(1):108–13. doi: 10.1016/j.coph.2005.11.003. Epub 2005 Dec 22. 39. Cheng JK, Chiou LC. Mechanisms of the antinociceptive action of gabapentin. J Pharmacol Sci 2006;100(5):471–86. doi: 10.1254/jphs.cr0050020. Epub 2006 Feb 11. 40. Peckham AM, Ananickal MJ, Sclar DA. Gabapentin use, abuse and the U.S. opioid epidemic: The case for reclassification as a controlled substance and the need for pharmacovigilance. Risk Manag Healthc Policy 2018 Aug;11:109–16. doi: 10.2147/RMHP.S168504. 41. Howden CH. Clinical pharmacology of omeprazole. Clin Pharmacokinet 1991 Jan;20(1):38–49. doi: 10.2165/00003088-199120010-00003. 42. Israel DM, Hassall E. Omeprazole and other proton pump inhibitors: Pharmacology, efficacy and safety with special reference to use in children. J Pediatr Gastroenterol Nutr 1998 Nov;27(5):568–79. doi: 10.1097/00005176199811000-00014. 43. Furuta T, Ohashi K, Kobayashi K, Iida I, Yoshida H, Shirai N, et al. Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans. Clin Pharmacol Ther 1999 Sep;66(3):265–74. doi: 10.1016/S0009-9236(99)70034-2. 44. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia 2017 Sep;60(9):1577– 1585. doi: 10.1007/s00125-017-4342-z. Epub 2017 Aug 3. 45. U.S. Food and Drug Administration. Metformin.

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www.accessdata.fda.gov/drugsatfda_docs/ label/2006/021748s002lbl.pdf. 46. Pradeep AR, Patnaik K, Nagpal K, Karvekar S, Guruprasad CN, Kumaraswamy KM. Efficacy of 1% metformin gel in patients with moderate and severe chronic periodontitis: A randomized controlled clinical trial. J Periodontol 2017 Oct;88(10):1023–1029. doi: 10.1902/jop.2017.150096. Epub 2017 Jul 21. 47. Pradeep AR, Rao NS, Naik SB, Kumari M. Efficacy of varying concentrations of subgingivally delivered metformin in the treatment of chronic periodontitis: A randomized controlled clinical trial. J Periodontol 2013 Feb;84(2):212–20. doi: 10.1902/jop.2012.120025. Epub 2012 Apr 17. 48. Bodey GP, Nance J. Amoxicillin: In vitro and pharmacological studies. Antimicrob Agents Chemother 1972 Apr;1(4):358–62. doi: 10.1128/aac.1.4.358. 49. Spyker DA, Rugloski RJ, Vann RL, O’Brien WM. Pharmacokinetics of amoxicillin: Dose dependence after intravenous, oral and intramuscular administration. Antimicrob Agents Chemother 1977 Jan;11(1):132–41. doi: 10.1128/ aac.11.1.132. 50. Kaur SP, Rao R, Nanda S. Amoxicillin: A broad-spectrum antibiotic. Int J Pharm Pharm Sci 2011;3(3):30–7. 51. Handsfield HH, Wallace HCJF, Holmes KK, Turck M. Amoxicillin, a new penicillin antibiotic. Antimicrob Agents Chemother 1973 Feb;3(2):262–5. doi: 10.1128/ aac.3.2.262. 52. Salvo F, Polimeni G, Moretti U, Conforti A, Leone R, Leoni O, et al. Adverse drug reactions related to amoxicillin alone and in association with clavulanic acid: Data from spontaneous reporting in Italy. J Antimicrob Chemother 2007 Jul;60(1):121–6. doi: 10.1093/jac/dkm111. Epub 2007 Apr 21. 53. Baillargeon J, Holmes HM, Lin YL, Raji MA, Sharma G, Kuo YF. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med 2012 Feb;125(2):183–9. doi: 10.1016/j.amjmed.2011.08.014. 54. Zhang Q, Simoneau G, Verstuft C, Drouet L, Bal dit Sollier C, Alvarez J, et al. Amoxicillin/clavulanic acid-warfarin drug interaction: A randomized controlled trial. Br J Clin Pharmacol 2011 Feb;71(2):232–6. doi: 10.1111/j.13652125.2010.03824.x. 55. Clark NP, Dalate T, Riggs CS, Witt DM, Hylek EM, Garcia DA, et al. Analysis of warfarin drug-drug interactions with antibiotics in the ambulatory care setting. Blood 2013;122(21):1143. doi.org/10.1182/blood. V122.21.1143.1143. 56. Goa KL, Wagstaff AJ. Losartan potassium: A review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 1996 May;51(5):820– 45. doi: 10.2165/00003495-199651050-00008. 57. Siegl PK, Kivlighn SD, Broten TP. Pharmacology of losartan, an angiotensin II receptor antagonist, in animal models of hypertension. J Hypertens Suppl 1995 Jul;13(1):S15–21. doi: 10.1097/00004872-199507001-00002. 58. Rossi GP. Losartan metabolite EXP3179: An AT1-receptorindependent treatment strategy for patients with the metabolic syndrome? Hypertension 2009 Oct;54(4):710–2. doi: 10.1161/HYPERTENSIONAHA.109.138883. Epub 2009 Aug 17. 59. Al-Majed AR, Assiri E, Khalil NY, Abdel-Aziz HA. Losartan: Comprehensive profile. Profiles Drug Subst Excip Relat Methodol 2015;40:159–94. doi: 10.1016/

bs.podrm.2015.02.003. Epub 2015 Apr 9. 60. Guasti L, Zanotta D, Diolisi A, Garganico D, Simoni C, Gaudio G, et al. Changes in pain perception during treatment with angiotensin converting enzyme-inhibitors and angiotensin II type 1 receptor blockade. J Hypertens 2002 Mar;20(3):485–91. doi: 10.1097/00004872-20020300000024. T HE CORRE S P ON DIN G AU T HOR , Aviv Ouanounou, BSc, MSc, DDS, can be reached at aviv.ouanounou@dentistry. utoronto.ca.

RM Matters

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Handling Conflicts With Confidence: Tools To Reduce Tension and Risk TDIC Risk Management Staff

n 2020 alone, The Dentists Insurance Company’s Risk Management Advice Line received 18,018 calls from dentists seeking support to navigate practice challenges. It’s a number that illustrates the myriad conflicts dentists navigate today as well as the profound need for tools to help them expertly de-escalate potential crises. Through the Advice Line, experienced analysts provide guidance to TDIC policyholders and members of dental associations in the states the insurance company serves — consulting on everything from COVID-19 pressures to employment concerns to problematic patient situations. Regardless of the topic, a common theme across the thousands of calls is a lack of confidence or comfortability in resolving conflicts. In fact, dentists sometimes ask the Risk Management analyst if they would be willing to speak to a patient or employee on their behalf. However, it’s the analyst’s role to provide the education, support and preventive advice to empower the dentist to independently engage in those conversations. The ability to resolve conflicts comes more naturally for some than for others, but many people avoid, delay or, at the very least, greatly dislike disagreements.

What’s keeping you from conflict resolution? The pull of procrastination

When we hold the false premise that all conflict is bad, of course we want to avoid it. However, the absence of conflict isn’t harmony, it’s apathy. When patients or staff speak their minds, it’s usually because they care. As Advice Line calls, claims and cases illustrate, avoiding conflict only allows the conflict to grow. We must understand that conflict will not resolve on its own. “Non-procrastinators focus on the task that needs to be done,” volitional

psychologist Joseph Ferrari, PhD, explained in an interview with the American Psychological Association. “They have a stronger personal identity and are less concerned about what psychologists call ‘social esteem’ — how others like us — as opposed to self-esteem, which is how we feel about ourselves.”

that is not in the practice’s best interest, simply to preserve their likeability. When approaching a situation with an intention of a resolution, rather than a win, it’s possible to disagree without being disagreeable. As author Max Lucado said, “Conflict is inevitable. Combat is optional.”

The aspiration to be agreeable

Trusting relationships among practice teams and between practices and their patients are built over time. Have you fostered an environment where staff can disagree without fear of hostility or being seen as disloyal? High-performing

It’s natural to want to be nice and kind, especially when sustaining relationships with staff and patients over many years. However, a dentist or office manager will often support an agreement or compromise

The lack of psychological safety

answers

From one-on-one risk management advice by phone to informed consent forms to expert-led seminars, we’re here to help you practice with confidence. We are The Dentists Insurance Company. Learn more at tdicinsurance.com/rm

Protecting dentists. It’s all we do.

800.733.0633 | tdicinsurance.com | Insurance Lic. #0652783

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teams provide channels for feedback, encourage conversation, value reliability and hold each other accountable.

so there is no misunderstanding about the source of conflict.

would create a disruption for my practice as well as other employees or patients.”

The tendency to take things personally

Be empathetic.

Whether at home, in the practice or out in the world, we tend to judge others by their actions and ourselves by our intentions. Others do the same. In the case of an employee who is late to work, the dentist judges the action and the impact to the schedule. The employee judges their own intentions and everything they’ve done — fighting traffic, getting kids to school, skipping breakfast — to try to make it to work on time. While the intention doesn’t excuse the action, an attempt to see both sides will facilitate more productive, solutionoriented discussions. Empathy also extends to saying thanks to employees for positive contributions of every size and offering sincere apologies when you’re in the wrong.

Be objective.

In the heat of conflict, we can be so busy disliking each other that there’s no energy left for productive debates. The truth is that when a personal conflict exists, every conflict large and small is seen in a negative light. Evaluate conflicts with objectivity: Is the issue centered around a task or issue, a pattern of behavior or truly the relationship? When every issue is interpreted as personal, our egos and self-esteem affect our ability to successfully resolve them.

Strive for these five principles to mitigate and de-escalate conflict: Be clear.

Overgeneralization can increase drama. For example, “You’re always late to work” is a broad statement that invites defensiveness. “I’m concerned that you’ve been about 30 minutes late the past three Fridays” is a specific, factsbased example. Alternately, to preserve likeability, communications may be so vague that both sides are left with different interpretations. If the dentist remarks on the employee’s lateness, even if there’s no specificity or follow through, the dentist may feel like they’ve addressed the issue and the employee may feel like they’re off the hook. This lack of clarity means a conflict is likely to occur in the future if the employee is late again. With patients, clarity comes with listening to concerns firsthand, not deflecting issues or delegating them to staff. Patients, just like everyone else, want to feel heard. Allow them to voice their concerns without interrupting or speculating on what may be driving the issue. Listen attentively to the patient and then repeat back your understanding of their concern 270 APRIL

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Be patient.

Living with unresolved conflict can be stressful but rushing to a solution rarely bears long-term gain. When a patient or employee has made a demand or offered a solution that you may not be able to accept in its current form, explain that you will need time to consider their request and return your decision. Understand that the individual with whom you’re working through the conflict may also need time to consider their answer to your proposed solution. However, if a patient’s demand is unreasonable, such as never scheduling a specific staff member on the day that they come in for their appointments or demanding exorbitant compensation, it is fair to answer at the time. Give a measured response that keeps the discussion open to reasonable demands, such as, “I understand that you are unhappy, but I don’t feel that your request is truly a fair assessment of the events,” or “I don’t feel it’s reasonable to ask me to make adjustments that

Easier said than done, isn’t it? How the message is being delivered and who it is delivered by often determines how we’ll engage more than the content. Taking a calm, respectful approach and, if needed, finding a private place to talk helps create the space for an objective discussion. When struggling to approach or engage in a conflict, start with the facts. No need to bring up past conflicts unless there is an established pattern of issues. View the situation as an opportunity to analyze the point of conflict, share your observations and listen to the other perspective before pursuing a resolution.

Be curious.

Empathy doesn’t mean making assumptions about others’ experiences. Listen first, engaging the patient or employee with questions to understand their perspective. Your curiosity can help de-escalate rapid escalation of conflict. For the late employee, an approach could be, “I’ve observed that you’re on time for most of your shifts, but not for the last few Fridays. Is there something going on that day that we can talk about?” Once you’ve heard the employee’s side, invite their input in finding a solution. Conflicts in the dental practice are inevitable. By addressing conflicts early and reframing them as an opportunity to productively address unresolved issues, you can better protect your practice. n The Dentists Insurance Company’s Risk Management Advice Line is a benefit available at no cost to CDA members, as well as to policyholders protected by TDIC. To schedule a consultation, visit tdicinsurance.com/RMconsult or call 800.733.0633.

Regulatory Compliance

C D A J O U R N A L , V O L 4 9 , Nº 4

Required Employee Training CDA Practice Support

mployers are required to provide employees with specified training. Most training must be done soon after an employee starts working for an employer and whenever the law changes or an employer changes their policies, procedures or equipment. Certain training must be provided annually or biennially. Methods to provide required training can vary. For most training, the employer is not required to use an outside trainer. Safety training is permitted to occur offsite as long as facility-specific information is provided to employees in conjunction with the training. Required training must be provided during working hours and at no cost to the employee. The required training described in this article does not include the mandated courses for unlicensed dental assistants or the continuing education requirements for license renewal. Required training must be documented. Training documentation should include a brief description of subjects covered, date of training, printed names, job title and signatures of individuals trained. List instructional aids if used. Bloodborne pathogens training documentation must identify the trainer and their qualifications. Except for HIPAA training, retain training documents for three years or until the employee completes new training, whichever is longer. HIPAA training documentation must be retained for six years or until the employee completes new training, whichever is longer.

New Employee Training

Training on the dental practice’s privacy and security policies and procedures should take place before a new employee starts to work or has access to patient information. If a new employee will have potential exposure to blood or saliva, then bloodborne pathogens training should be completed within a few days of starting work. Injury and illness prevention, which includes COVID-19 prevention, hazard communication, radiation safety and regulated waste management training, should be provided to the new employee within the first month of starting work. New employees may be instructed verbally on office procedures and should have the opportunity to review the Cal/ OSHA-required written plans and to ask questions of the trainer. Training topics include but are not limited to: ■ Location of exits, fire extinguisher (if one is available), eyewash station and first-aid kit. ■ Location and use of personal protective equipment for infection control when handling chemicals or working with lasers or UV light. ■ Procedure for screening patients for aerosol-transmissible diseases such as COVID-19. ■ Procedure for reporting employee injuries, potential hazards and unsafe work practices in the dental office. ■ Identification of chemical, radiation, infectious and other hazards in the office, plus procedures and equipment utilized to prevent exposure to the hazards.

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Location of safety data sheets and explanation of the hazard communication plan, labeling of containers, pictograms and signal words. Location of regulated waste containers and procedures for disposal. Maintenance of amalgam separator and other equipment.

Training Frequency

Sexual harassment training must be provided by employers with five or more employees to a new employee within the first two years of employment and every two years afterward. Bloodborne pathogens/exposure control training is the only required training that must be provided annually to employees who are potentially exposed to blood or saliva during the course of their work. As stated earlier, sexual harassment training is required to be provided to an employee every two years. All other required training should be delivered soon after hire and when the applicable law changes, when the employer changes their policies, procedures or equipment or when the employer or supervisor believes additional training is necessary for an employee or employees.

Exposure Control Training vs. Infection Control C.E. Requirement Some individuals confuse the Cal/ OSHA-required bloodborne pathogens/ exposure control training with the dental board’s requirement to complete a board-approved infection control APRIL 2 0 2 1

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course for license renewal. They are not the same course, but the boardrequired two-hour course, which must be provided by a board-approved provider, can include elements of the Cal/OSHArequired training. There is not a time requirement for Cal/OSHA training. The Cal/OSHA bloodborne pathogens/exposure control training must include, at a minimum: ■ A copy and explanation of the regulation. ■ A general explanation of the epidemiology and symptoms of bloodborne diseases. ■ An explanation of modes of transmission of bloodborne pathogens. ■ An explanation of the employer’s exposure control plan and the means by which the employee can obtain a copy of the written plan. ■ An explanation of appropriate methods for recognizing tasks and other activities that may involve exposure to blood and other potentially infectious material (OPIM). ■ An explanation of the use and limitations of methods that will prevent or reduce exposure including appropriate engineering controls, administrative or work practice controls and personal protective equipment. ■ Information on the types, proper use, location, removal, handling, decontamination and disposal of personal protective equipment. ■ An explanation of the basis for selection of personal protective equipment. ■ Information on the hepatitis B vaccine, including information 272 APRIL

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on its efficacy, safety, method of administration, the benefits of being vaccinated and that the vaccine and vaccination will be offered free of charge. Information on appropriate actions to take and persons to contact in an emergency involving blood or OPIM. An explanation of procedures to follow if an exposure incident occurs, including the method of reporting the incident, the medical followup that will be made available and the procedure for recording the incident on the sharps injury log. Information on the postexposure evaluation and followup that the employer is required to provide for the employee following an exposure incident. An explanation of the signs and labels and/or color coding required. An opportunity for interactive questions and answers with the person conducting the training session.

Temporary Employees/Students/ Independent Contractors

HIPAA requires that covered entities such as a dental practice train all individuals who work at their locations and have access to or work with patient information on the entities’ privacy and security policies and procedures. This includes non-employees such as temporary employees, independent contractors and students. Sitespecific safety training must be provided to temporary employees. More information can be found in the CDA Practice Support resource “Required Employee Training” at cda.org. n

Regulatory Compliance appears monthly and features resources about laws that impact dental practices. Visit cda.org/ practicesupport for more than 600 practice support resources, including practice management, employment practices, dental benefit plans and regulatory compliance.

Ethics

C D A J O U R N A L , V O L 4 9 , Nº 4

‘Free/Politically Correct’ Speech in the Dental Office Denise Habjan, DDS

hat is appropriate speech in the dental office? Dentistry is an interactive and personal process. There is much more involved than just providing the actual services of dentistry. The teeth and mouth are attached to a living human being. Fortunately, none of us are robots. Clinical treatment of patients is just one aspect of dentistry. We also have families of patients, staff, venders, etc., with whom we interact daily. Communication is key. We communicate through words, mannerisms and actions. As health care providers, we strive to be caring, kind, compassionate and good listeners. We treat others as we want to be treated. Many would say to be successful you should treat all patients like family. We want those in our practice to feel comfortable and welcomed. Patients want to return to our practices for more than just the actual dental treatment. It’s the connections that we maintain with our patients and staff that keep patients coming back. From the first moment someone comes into the office and you ask them, “How are you doing today?” you do not know what response or questions you will get. But with that, how do we respond with the “charged” atmosphere that we seem to be in today? Everything, it seems, can be offensive to some and not others. How do we navigate this climate? Wikipedia defines “freedom of speech” as a principle that supports the freedom of an individual or a community to

articulate their opinions and ideas without fear of retaliation, censorship or legal sanction. “Political correctness” is a term used to describe language, policies or measures that are intended to avoid offense or disadvantage to members of particular groups in society. What can we use to guide us through this daily obstacle course? It is important to consider others’ potential perspectives by the way we speak and act. We need help running our offices smoothly. Guidance is needed to help reduce the stress that we are experiencing in our dental offices. How do we respond to pointed questions about our political views? How do we respond to questions that seem controversial and offensive? This does not apply to just politics, but just about all other topics as well. These are difficult questions; we run practices that treat patients and have staff to support as well. It is not realistic to expect to just treat likeminded people. Nor would we want to. And we can all agree on some topics and not others. Is it OK to disagree? Should we say so or not? So, “free speech” and “political correctness “in the dental office — how do we navigate this and maintain a healthy practice and our own personal sanity? As dentists, we do our best to practice dentistry, but it is more than that as we interact with other human beings all day long. Answers are not easy. It would be nice if we could truly appreciate the diversity and embrace with compassion and kindness the differences of opinion that we all have.

During these times, we can look to the CDA Code of Ethics’ principles of tolerance and integrity for guidance. Tolerance can be interpreted to expand beyond culture and ethical diversity and challenges dentists to simply recognize that “differences exist.” Integrity “requires the dentist to behave with honor and decency” and means the dentist recognizes when words or actions are in conflict with one’s values. If you value mutual respect and good communication with your patients and staff, you will consider a compatible response. What we can do is strive to truly do the best that we can as dentists and be mindful of others as ethically as we can. n Denise Habjan, DDS, is a practicing dentist in Santa Ana, Calif. She served on the CDA Judicial Council.

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Tech Trends

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A look into the latest dental and general technology on the market

Lenovo ThinkPad P15

(MSRP: $2,599, base model; $6,799 reviewed model, Lenvo) Laptop computers have become incredibly powerful, reliable and cost-effective to the point where many private practices choose to utilize them over desktops. Consumers are now faced with endless options from a multitude of manufacturers, and the top-of-the-line laptops guarantee unparalleled performance once the cost is paid … or do they? This review focuses on the new Lenovo ThinkPad P15 with a 12-core Intel Xeon processor, 32GB of RAM, 1TB SSD hard drive and the NVIDIA Quadro RTX 5000 graphics card. The ThinkPad P15 does not look fancy from the outside: Its matte black finish, 15-inch screen and less than 6-pound frame make it look like every other laptop out there, albeit a little thicker. Turn it on and its strengths shine through. The screen is an ultra HD OLED touchscreen display that’s been color calibrated, making every detail sharp. The speakers are Dolby Atmos certified and accentuate low-end sounds. The computer has absolutely no delay in response in normal tasks (e.g., word processing, web browsing, accessing electronic health records, playing video) and barely slows down at the most intense of tasks (e.g., 3D-model rendering, editing 4k video, etc.). Unlike Apple products, the P15 has a large number and diversity of peripheral ports from SD cards to USB-A. It is a dream of a computer … until it breaks down. Less than two hours into its use, external displays began flickering, the computer speed slowed to a crawl and audio began cutting in and out. After several hours with technical support, which was excellent and responsive, it was found that the P15 had a defective motherboard. Searching on Google revealed that this experience was not unique to this reviewer. At nearly $7,000, one would hope that this particular unit was a lemon and not a representation of the norm. While the P15 is an incredible machine with impressive specifications, it cannot be recommended due to questions about its reliability. — Alexander Lee, DMD

Logitech StreamCam ($169, Logitech) Many built-in cameras on laptops and mobile devices have basic support but cannot stream high-quality video due to size and formfactor constraints. The Logitech StreamCam is an external webcam created to meet the demands for excellent video streaming during the pandemic. The StreamCam has an impressive array of technical specifications, including 1080p HD video at 60 frames per second (fps), f/2.0 lens aperture with autofocus and auto-exposure, landscape or portrait mode and dual front-facing microphones. The webcam includes support for Open Broadcaster Software (OBS), XSplit and Streamlabs, which allows for seamless streaming on popular platforms. Individual monitor and tripod mounts are provided for flexible positioning options. Higher resolution and frame rates require a direct USB 3.1 Gen 1 Type-C connection to a Mac or PC with a 7th Gen Intel Core i5 or higher processor. When connected to the computer out of the box, the webcam is detected automatically and is available to use in any application without installing additional software. The default video quality with autoadjustment settings and landscape mode are spectacular when compared to most built-in webcams. However, in order to manually adjust settings or change between landscape or portrait mode, Logitech Capture software needs to be installed. At the time of this review, the Mac version of this software is in beta and computers with the new Apple M1 chip are not yet supported. Additionally, the webcam occasionally may produce random video artifacts or audio clipping during use. These random glitches can only be resolved by disconnecting and reconnecting the webcam to the computer. Logitech may provide a firmware update in the future to address these issues, and individual user experience may vary depending on hardware specifications and software installed. With remote videoconferencing as the standard for human interaction during the pandemic and in the foreseeable future, webcams have become important in facilitating conferences and social gatherings. The Logitech StreamCam aims to meet the demand for producing high-quality video to deliver personal expressions virtually. Although this webcam does deliver on its specifications, users may have a hit-or-miss experience depending on their personal setup and use. — Hubert Chan, DDS

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TOGETHER WE ARE LIMITLESS

A strong future takes all of us. Together, we’re successfully advocating on issues that impact your practice today and your profession tomorrow. From vaccine administration to financial relief to flexible C.E. during COVID-19, our dedicated legislative advocacy team ensures CDA members’ voices are heard. Join your dental community in action. Learn more at cda.org/advocacy.

IT’S A VERB.

Abigael Cho, DDS Member since 2020

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FOUR DAYS FOR MORE WAYS TO LEARN & EARN C.E. CDA Presents The Art and Science of Dentistry returns as an innovative virtual convention this spring. From the convenience of your home or office, take part in engaging education — from required C.E. to new insights on clinical care and practice management. Come get guidance and connect with peers and exhibitors through our dynamic digital platform. • FOUR DAYS of exciting education • LIVE C.E. for the whole dental team • 60+ COURSES by leading speakers • INTERACTIVE, real-time exhibit hall Join us May 13-16, 2021. Registration is open right now at cda.org/cdapresents.

MAY 13–16, 2021 VIRTUAL CONVENTION