7
Head and Neck Cancer
Amber L. Watters, DDS, MPH, MS
Heidi J. Hansen, DMD
Ashish A. Patel, MD, DDS, FACS
Joel Epstein, DMD, MSD, FRCD(C), FDS RCS(E)
Figure 7‐1 The oral cavity and oropharynx. Source: Copyright © 2011 American Dental Association. All rights reserved.
Reproduced with permission of Elsevier.
Oral cancer is a broad term that includes a number of malignant diagnoses that present in the oral region. Even though the management and prognosis may be different among types and stages of oral cancer, the condition always has a dramatic impact on the patient’s life. The cancer and its therapy are associated with morbidities that may negatively affect quality of life, both during cancer therapy, in the immediate period after treatment, and continuing throughout the life of the patient.
Older literature often combines oral squamous cell carcinoma (OSCC) and oropharyngeal carcinoma (OPC), making the evaluation of epidemiology, pathogenesis, and outcomes difficult to assess between the two diseases, and it is now recognized that OSCC and OPC must be evaluated individually. To develop a uniform baseline for discussion, the anatomic domains are presented in Figure 7-1. The oral cavity includes the lips, the labial and buccal mucosa, the anterior two-thirds of the tongue, the retromolar pad, the floor of the mouth, the gingiva, and the hard palate. The oropharynx includes the palatine and lingual tonsils, the posterior one-third (base) of the tongue, the soft palate, and the posterior pharyngeal wall. The nasopharynx extends above the oropharynx and the glottis and larynx below.
This chapter will provide a review of various types of oral and oropharyngeal malignant diseases, with a focus on OSCC and OPC. It will also review other cancers in the head and neck, including nasopharyngeal cancer, paraneoplastic syndromes, and head and neck malignant disease in AIDS. This is a topic that is highly relevant to all healthcare professionals caring for patients during all phases of cancer treatment, from detection to diagnosis, precancer treatment dental care and prevention, and managing oral and dental care for cancer survivors.
EPIDEMIOLOGY
OSCC and OPC represent the sixth most common cancer worldwide.1 The global incidence of OSCC and OPC is 4.2% of all cancers (754,252) per year, which is expected to increase by 62% to 856,000 by 2035.2 Worldwide over 354,864 new cases and 177,384 deaths were attributed to OSCC in 2018.3
In the United States, OSCC and OPC affect 10.8 of every 100,000 individuals, and 7.2 of every 100,000 individuals will have oral cancer.2 The estimated new oral and oropharyngeal cancer cases in the United States for 2019 were calculated to be 53,000, with estimated deaths of 10,860.4 During their lifetime 1.1% of the US population will be diagnosed with oral cavity and oropharyngeal cancer. The American Cancer Society (Cancer.Net) reports that 5-year survival in the United States is now over 62%.5 This is an improvement in the relative survival compared to 1950–1954, during which relative survival was calculated to be 46%.6
The statistics are similar throughout North America but vary around the world; for example, in Hungary the incidence is up to 21.1 cases per 100,000 population.7 In Southeast Asia the prevalence of oral cancer is high. Oral cancer is ranked one of the sixth most frequent malignancies in Asia, where nearly 274,300 new cases occur annually. The incidence rate is more than 10 per 100,0008 and it may reach an annual incidence rate of 21.4 per 100,000 individuals in some districts of India.9,10 Cultural habits, including betel quid chewing, alcohol consumption, and reverse smoking, as well as low socioeconomic status and low consumption of fruits and vegetables, contribute to this high prevalence. The trend differs among countries in this region (it increases in Pakistan and decreases in the Philippines and Sri Lanka) and even varies among provinces of the same country (Thailand).8
The majority of oral cancers are squamous cell cancers. Other malignant diseases that can occur in the oral cavity include tumors of the salivary glands, lymph nodes, bone, and soft tissue.
Approximately 95% of oral cancer occurs in people older than 40 years, with an average age at diagnosis of approximately 60 years.11 OSCC at a young age and even in pediatric patients has however been reported.12
The majority of oral cancers involve the lateral borders and base of the tongue. The lips, gingiva, dorsal tongue, palate, and salivary glands are less common sites. Primary squamous cell carcinoma (SCC) of bone is rare; however, a tumor may develop from epithelial rests and from epithelium of odontogenic lesions, including cysts and benign lesions. Individuals who have had a previous cancer are at high risk of developing a second primary oral cancer. African Americans in the United States have a lower risk of developing OSCC and OPC than Caucasians (9.6 vs. 11.2 per 100,000 population).13
Data published specifically for OPC associated with human papillomavirus (HPV) infection showed increased incidence, most of which is related to a rise in incidence in Caucasian males.14,15 In contrast, the incidence in black males has not increased.2 Analysis of tissues in national registries during the years 1984–2004 showed that the increase in the population-level incidence of oropharyngeal cancers in the United States since 1984 is caused by HPV infection.16,17 HPV is primarily associated with OPC, with many fewer HPV-positive tumors in the oral cavity, nasopharynx, and larynx. Despite the changing risk factors for OPC, there is no evidence that detection of high-risk HPV can predict the development of oropharyngeal cancer accurately, as the majority of individuals clear the virus. Interesting findings suggest that tonsillectomy may reduce the incidence of OPC, and decreasing tonsillectomies conducted between 1970 and 2009 may also reflect the period of increasing HPV infection and OPC.18
A risk prediction model incorporating OSCC/OPC risk factors, including age, sex, race, smoking, alcohol, lifetime sexual partners, and HPV infection, predicted the following 1-year risks: 21.1/100,000 for older individuals (65–69-year-olds), 13.9/100,000 for men, 10.4/100,000 for Caucasians, 18.0/100,000 for smokers >20 pack years, 18.4/100,000 for heavy alcohol users, and 140.4/100,000 for oncogenic HPV, showing the relative risks of each component of the model.19 Risk of oral cancer is moderately increased in immunocompromised patients (transplants and HIV infection), was associated with duration of immunosuppression, and was highest in those HIV infected.20
Tumors of the salivary glands, the majority of which involve the parotid glands, represent less than 5% of all head and neck tumors. Approximately two-thirds of these are benign mixed tumors (pleomorphic adenomas). In order of decreasing frequency, malignant salivary gland tumors are mucoepidermoid carcinoma, adenoid cystic carcinoma, adenocarcinoma, SCC, malignant pleomorphic adenoma, undifferentiated carcinoma, lymphoma, melanoma, and a mixed group of sarcomas. Malignant salivary gland tumors are more common in the submandibular, sublingual, and minor salivary glands than in the parotid glands.21
ORAL CANCER CLASSIFICATION
Oral cancer nomenclature reflects the histopathologic characteristics of the lesion. In order to facilitate communication between healthcare providers, a classification system was established by the World Health Organization/International Agency for Research on Cancer (WHO/IARC).22 The classification system was most recently updated in 2017 based on advances in technology and outcome data.
According to the WHO/IARC classification of tumors, the morphology of the cells and the tissue architecture as seen in light microscopy are used to define the neoplasm, which may correlate with the biology and behavior of the cancer.
Publications within the WHO/IARC classification of tumors reference books (“Blue Books,” 4th edition) refer to cancer of the oral cavity, oropharynx, cancer of the salivary glands, and odontogenic tumors. Notable changes in this 2017 update underscore the distinct pathologic differences between OSCC and OPC. Tumors of the oropharynx (base of tongue, tonsils, and adenoids) are further delineated into HPV-positive and HPV-negative SCC. HPV-positive tumors are no longer graded histologically. These changes underscore the epidemiologic trends demonstrated by the changing demographics, anatomic site, and prognostic outcomes that make up the current landscape of head and neck cancer.
SQUAMOUS CELL CARCINOMA OF THE ORAL CAVITY AND OROPHARYNX
Etiology and Risk Factors
The incidence of oral cancer is age related, which may reflect time for the accumulation of genetic changes and duration of exposure to initiators and promoters. These include chemical and physical irritants, viruses, and hormonal effects. In addition, decreased immunologic surveillance over time may be another explanation for the age relation. Furthermore, immunosuppressed patients following solid organ and hematopoietic stem cell transplantations, patients treated with chemotherapy, and HIV patients have an increased risk.
Tobacco and Alcohol
Tobacco products and alcohol are acknowledged risk factors for oral and oropharyngeal cancer. Tobacco contains potent carcinogens, including nitrosamines, polycyclic aromatic hydrocarbons, nitrosodiethanolamine, nitrosoproline, and polonium. Tobacco smoke contains carbon monoxide, thiocyanate, hydrogen cyanide, nicotine, and metabolites of these constituents. Nicotine is a powerful and addictive drug. Epidemiologic studies have shown that up to 80% of oral cancer patients were smokers.11 In addition to the risk of primary cancers, the risk of recurrent and second primary oral cancers is related to continuing smoking after cancer treatment. Of patients who were observed for 1 year, 18% developed a recurrence or a second primary oral cancer, and those who continued to smoke had a 30% risk.23 The effect of smoking on cancer risk diminishes 5–10 years after quitting.
Most studies have focused on cigarette use; however, other forms of tobacco use have been associated with oral cancers. Benign hyperkeratosis and epithelial dysplasia have been documented after short-term use of smokeless tobacco products, and it is implied that chronic use will be associated with an increasing incidence of malignant lesions.11,24 The potential risk of oral cancer with cannabis is unclear as data are inconsistent, with some reports suggesting decreased risk of cancer associated with the anti-inflammatory and antioxidant properties of cannabinoids. Route of ingestion (smoking, vaping, or edible formulation) and potential contaminants along with confounding variables make the relationship between cannabis and head and neck cancer currently indeterminate.25,26
All forms of alcohol, including “hard” liquor, wine, and beer, have been implicated in the etiology of oral cancer. While this topic is difficult to study for many reasons, several studies identified subpopulations in which alcohol is not a risk factor for oral cancer, such as nonsmoking, non-betel-chewing participants or those with the MTHFR TT genotype in Asians.27,28 In contrast, other studies identified subpopulations at a higher risk for oral cancer following high-dose long-lasting exposure to alcohol, such as participants with ADH1C*1/*2 (Caucasians), ADH1C*1/*2 or ADHA1C*2/*2 (Asians), and ALDH2*2 (Asians).29 The combined effects of tobacco and alcohol result in a synergistic effect on the development of oral cancer. The mechanisms by which alcohol and tobacco act synergistically may include dehydrating effects of alcohol on the mucosa, increasing mucosal permeability, and the effects of potential carcinogens in alcohol or tobacco. Various enzymatic pathways were suggested as having a role in the mechanism of the synergistic effect of smoking and alcohol on the oral mucosa. Alcohol in small amounts has been shown to have cardioprotective effects and increases high-density lipoprotein levels. The definition of moderate alcohol intake is likely related to individual factors, therefore making population-level recommendations for safe intake not possible.24
Areca Nut and Betel Leaf
People who use betel quid, pa(a)n masala, Gutk(ha)a, Catechu gum, or Supari, with or without added tobacco, are at a higher risk for developing oral cancer. In parts of Asia and Southeast Asia (e.g., India, Taiwan), use is historically widespread and accounts for the higher incidence of oral cancer. This habit is often continued in immigrant communities in the United States and Canada and providers outside of India and Asia should be familiar with the effects of this carcinogen: oral submucous fibrosis of the buccal mucosa and periodontium may develop secondary to alkaloid damage to fibroblasts. The resulting fibrosis may cause a decreased intraoral aperture, interfering with speech, swallowing, and oral care, which may lead to an increase in periodontal disease risk. Submucous fibrosis is considered a premalignant condition and other deleterious health effects including increased risk of non-head and neck primary cancers have been reported.30
Human Papillomavirus
HPVs are DNA viruses that infect various epithelial surfaces. There are more than 120 types of HPV. HPV 16, 18, 31, 33, and 35 are considered high-risk subtypes due to their association with malignant tumors. HPV 16 alone is associated with about 90% of HPV-positive oropharyngeal cancers. The virus penetrates the host cell and integrates into the host cell genome, where it can replicate. Malignant transformation occurs through the expression of two HPV viral oncogenes, E6 and E7, which downregulate p53 and Rb, two critical cell regulators of cell cycle progression. HPV-related head and neck squamous cell carcinoma (HNSCC) continue to express p16, unlike HPV-negative tumors, which makes p16 a marker for HPV infection.31 There are many unanswered questions about the biology of HPV infection, which include clearance versus persistence of virus, latency and carcinogenesis, site localization, recurrence, and second primary cancers. This is discussed further in the section on oncoviruses.
HPV is transmitted by direct contact, primarily by means of vaginal, anal, and oral sex. Risk of developing HPV-positive oropharyngeal cancer increases with an increasing number of self-reported lifetime sexual partners (oral and vaginal), younger age at first sexual activity, and history of having a same-sex partner; in addition, the level of risk can vary according to tumor site.32 It is important to note that these findings are related to oropharyngeal carcinoma, whereas in oral cancer HPV is not well defined as a risk factor.
Nutritional Factors
Low consumption of fruits and vegetables and high consumption of meat, tobacco, and alcohol is associated with an increased risk of cancer. Foods high in vitamins A, C, E, and selenium have antioxidant protective effects, particularly for epithelial cancers. High abdominal adipose composition combined with low consumption of nutritionally dense foods is a concern for increased cancer rates in Western countries.33
Lycopene and beta carotene may play a role in reducing the risk of premalignant lesions of the oral cavity. This hypothesis is based on population studies in which deficiency was associated with a risk of SCC, and on studies of vitamin A and carotenoid supplementation, as well as on studies of reduction in carcinogenesis in animal models. Some reports have demonstrated that vitamin A may cause regression of premalignant leukoplakia.34
Other Risk Factors
There is conflicting evidence on the causality of other risk factors related to oral health, including alcohol-based mouthwashes, poor dental status, denture use, chronic mucosal trauma, and microorganisms. These factors combined with exposure to known carcinogens likely work in a synergistic fashion. The role of local trauma in the development of oral cancer remains controversial.35,36 It is possible that chronic trauma, in the presence of other risk factors and carcinogens, may promote the transformation of epithelial cells, as has been demonstrated in animal studies.
In lip cancer, sun exposure, fair skin, pipe smoking, and alcohol are identified risk factors.37 Recurrent herpes simplex virus of the lip has not been associated with increased cancer risk.
Environmental exposure to indoor and outdoor pollution from wood smoke and coal combustion, leading to inhaled toxins such as mercury, lead, sulfur dioxide, nitrogen, and other particulates, is related to numerous deleterious health effects globally. The IARC has classified air pollution as a carcinogen and it is a leading environmental cause of cancer deaths.38
Certain inherited cancer syndromes show an increased risk for oral cancer. For example, oral cancer is one of the cancers that are typical for patients with Fanconi anemia. Cowden syndrome, xeroderma pigmentosum, and dyskeratosis congenita were reported in association with oral cancer as well.39
Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of developing secondary neoplasms, particularly leukemias and lymphomas, which may manifest in the oral tissues. Likewise, OSCC has been reported as having up to a 20-fold increase in risk in these patient populations.40–42 OSCC after an extended period of immunosuppression post transplantation is documented as having similar molecular changes as seen in nonmedically induced immunosuppression.43 Oral cancer may behave more aggressively in patients post HSCT with chronic graft-versus-host disease and associated immunosuppression. Other immunosuppressed patients show increased risk for oral cancer as well, such as patients after liver transplantation.44
Oral Potentially Malignant Disorders
The WHO listed several oral conditions as having the potential to transform into oral cancer, including lichen planus, leukoplakia, discoid lupus erythematosus, inherited disorders, tobacco-related lesions, erythroplakia, actinic cheilitis, and submucous fibrosis.23 Under the term “leukoplakia,” it is worthwhile mentioning proliferative verrucous leukoplakia, which behaves more aggressively than other leukoplakias and has a high risk of progression to SCC.45 Within the oral cavity, leukoplakia, erythroleukoplakia, and speckled leukoplakic lesions may have dysplastic elements within the clinically identifiable lesion. Keratotic epithelium with dysplasia has a 3–5 times increased risk of malignant transformation with severe dysplasia.46
The classification of oral potentially malignant disorders (OPMDs) takes into account that a field change in clinically normal-appearing tissues may occur in a patient with a diagnosed OPMD. Most patients will not have a specific diagnosis and many may have an isolated lesion. Clinical and histologic features may help the oral medicine provider stratify risk for malignant progression. These high-risk factors include large size, nonhomogeneous texture, red or speckled in color, tongue or floor of mouth location, tobacco use, and histologic severe dysplasia.
Pathogenesis
Carcinogenesis is a genetic process that leads to a change in molecular function, cell morphology, and, ultimately, cellular behavior. Carcinogenesis is not limited to the epithelium but involves a complex epithelial, connective tissue, and immune function interaction.
Major genes involved in OSCC include oncogenes and tumor suppressor genes (TSGs). Regulatory genetic molecules may be involved as well.47 The genetic changes may be reflected in allelic loss or addition at chromosome regions corresponding to proto-oncogenes and TSGs, or epigenetic changes such as deoxyribonucleic acid (DNA) methylation or histone deacetylation. Extracellular enzymes, cell surface molecules, and immune function play a role in the development and spread of oral cancer; viruses and carcinogens are involved as well.48
While the principal studies have been related to epithelial changes, some of the components listed can constitute a complex environment that suggests an epithelium-connective tissue theoretical model. For example, the interplay of extracellular enzymes, cell surface molecules, growth factors, and the immune system leads to epithelial–connective tissue interaction. According to this model, mucosal differentiation and maturation of epithelial cells represent an epithelial and connective tissue bidirectional process that may be involved in carcinogenesis.
Oncogenes
Oncogenes may encode for growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. Although proto-oncogenes increase cell growth and effect differentiation and are likely involved in carcinogenesis, few have been consistently reported in HNSCC. Proto-oncogenes associated with HNSCC include ras (rat sarcoma), cyclins, myc (myelocytomatosis), erb-b (erythroblastosis), bcl (B-cell lymphoma), int-2, CK8, CK19, and epidermal growth factor receptor (EGFR).47,49 Each of these oncogene families has several genes and isoforms with potential roles in carcinogenesis. For example, the ras family has three genes (Hras, Kras, Nras) and represents one of the most mutated oncogenes in human cancer, including oral cancer.50
Tumor Suppressor Genes
TSGs negatively regulate cell growth and differentiation. Functional loss of TSGs is common in carcinogenesis and in OSCC. Both copies of a TSG must be inactivated or lost for loss of function (the “two-hit” hypothesis). Chromosomes are numbered (1 to 23), and the arms of each chromosome are divided by the centromere into a short arm (designated P) and a long arm (designated Q). TSGs have been associated with sites of chromosome abnormalities where loss of genetic nucleic segments has been reported to commonly involve chromosome arms 3p, 4q, 8p, 9p, 11q, 13q, and 17p. TSGs involved in HNSCC are P53, Rb (retinoblastoma), and p16INK4A. Other candidates include FHIT (fragile histidine triad), APC (adenomatous polyposis coli), DOC1 VHL (gene for von Hippel-Lindau syndrome), and TGF-R-II (gene for transforming growth factor type II receptor).47
Gene-Regulating Proteins
Part of the oncogenic gene regulation is performed by transcription factors. These are proteins binding to DNA sequences to permit or inhibit co-binding to RNA polymerase, which in turn regulates the activation of the DNA-segment respective gene. Transcription factors that were identified from oral tumors and their potential contribution to oral cancer are listed in Table 7-1.50
Loss of Heterozygosity
Loss of heterozygosity (LOH) or allelic loss has been studied in oral premalignant lesions and predicts the malignant risk of low-grade dysplastic oral epithelial lesions.51 The importance of allelic loss has been shown in retrospective and cross-sectional studies and confirmed in a prospective study of patents with dysplasia, where lesions with allelic loss at 3p, 9p, and 17p predict risk of progression to SCC, even in histologically benign tissue or tissue with mild dysplasia. This is of importance, as the majority of potentially malignant oral lesions (hyperplasia, mild and moderate dysplasia) do not progress to cancer. Lesions that progress to SCC appear to differ genetically from nonprogressing lesions, even though they may not demonstrate different histomorphologic findings.
Molecular analysis therefore may become necessary in diagnosis. LOH on 3p and/or 9p is seen in virtually all progressing cases. LOH on 3p and/or 9p has a 3.8 times relative risk of developing SCC, and if additional sites of LOH are present (4q, 8p, 11q, 13q, or 17p), there is a 33-fold increase in risk of progression to cancer. Accumulation of allelic loss is seen in progressing lesions, and the majority of progressing dysplasias have LOH on more than one arm (91% vs. 31% of nonprogressing dysplasias); 57% have loss on more than two arms (vs. 20% of dysplasias without progression). LOH on 4q, 8p, 11q, 13q, and 17p is common in severe dysplasia and carcinoma in situ as well as SCC.52,53
Table 7‐1 Commonly involved oncogenic transcription factors propelling oral cancer.
Source: Adapted with permission from Yedida GR, Nagini S, Mishra R. The importance of oncogenic transcription factors for oral cancer pathogenesis and treatment. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116(2):179–188.
| OTF | Oncogenic potential in OSCC |
| AP-1 | Overexpression, nuclear expression increased according to degree of dysplasia, lymph node metastasis, increased transcriptional activity |
| NF-κB | Differential expression, activation, proliferation, malignant transformation, invasion |
| c-Myc | Overexpression, DNA amplification, DNA binding activity, progression of oral cancer |
| STAT | Early overexpression and activated form of transcription factor, active in OSCC |
| β-catenin | Nuclear overexpression, oral cancer progression, metastasis |
| Snail | Overexpression, activation, invasion, correlated with EMT |
| HIF1α | Overexpression, progression, expression correlates with poor prognosis, invasion |
| Mutated p53 (GOF) | Inactivated protein, GOF of mutant p53 propel mitosis by expressing cyclin A and cyclin B, GOF leads to shorter disease-free survival, prevention apoptosis after DNA damage, chemoresistance, disease progression |
EMT, epithelial–mesenchymal transition; GOF, gain of function; OSCC, oral squamous cell carcinoma; OTF, oncogenic transcription factor.
Hypermethylation
The role of promoter hypermethylation of CpG islands is being investigated in OSCC, as methylation of epigenetic DNA has been shown to result in a loss of function in some genes involved in cell cycle regulation and DNA repair that may lead to loss or change in TSGs involved in carcinogenesis. Changes in DNA methylation of six genes and a significantly higher frequency of methylation in a number of TSGs, including cyclin A1 and p16 promoter sequences, have been seen. Mitochondrial DNA (mtDNA) content increases with oxidative damage as possible compensation to mitochondrial dysfunction. MtDNA as assessed by polymerase chain reaction for specific mitochondrial genes was shown to increase with severity of dysplasia and in SCC. These findings support the model of accumulation of genetic alterations as mucosal disease progresses from benign to dysplasia and potentially to SCC, and the contention that mtDNA increases with histologic grade.54,55
MicroRNA
MicroRNAs are small segments of nonencoding single-stranded RNAs that mediate gene expression at the post-transcriptional level by mRNA degradation or translational repression. Aberrant microRNA may disrupt the normal regulation and lead to malignancy. MicroRNAs function either as oncogenes or as tumor suppressors and are suggested to play a role in oral cancer.56
Extracellular Enzymes
SCC primarily spreads by direct local extension and by regional extension, primarily via the lymphatics. Regional spread in the oral mucosa may occur by direct extension and possibly by submucosal spread and results in wide areas of involvement. Production of type I collagenase, heparanase, prostaglandin E2, and interleukin-1 and connective tissue growth factor (CTGF) may affect the extracellular matrix, and motility of epithelial cells may allow invasion.57,58 Changes in the basement membrane, such as the breakdown of laminin and collagen, occur with invasion. Matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase play a role in cancer initiation and development and have prognostic significance.59 The initiation or progression of oral cancer may also be associated with polymorphism of the vascular endothelial growth factor (VEGF) gene.60,61 Understanding the biology of invasion by malignant cells may lead to additional approaches to diagnosis and management.
Cell Surface Changes
Changes in cell surface receptors and major histocompatibility class I and class II antigens have been seen and may indicate that immune surveillance and immune function may be affected in patients with oral cancer. Other cell surface changes include a loss of cytoplasmic membrane binding of lectins, which has been shown to correlate with the degree of cellular atypia.
Intercellular adhesion molecules may play a role in tumorigenesis and perineural invasion. Integrin is a cell adhesion receptor and is often associated with altered expression in tumors as well as with malignant transformation. Alterations in cell-bound immunoglobulins and circulating immune complexes are detectable, but the importance of these changes is unclear.
Immunosuppression
The development of malignant disease at a higher rate in immunosuppressed patients indicates the importance of an intact immune response. Mononuclear cell infiltration correlates with prognosis, and more aggressive disease is associated with limited inflammatory response. Total numbers of T cells may be decreased in patients with head and neck cancer. In addition, the mixed lymphocyte reaction is reduced in some patients, and a diminished migration of macrophages has been demonstrated. Clusters of differentiation 8 (CD8) lymphocytes (T-suppressor cells) predominate tumor infiltrates, suggesting that immunosuppression is associated with progression of disease. Programmed cell death-1 (PD-1) is currently the target of many cancer immunotherapy agents aimed at interference with specific immune checkpoints. This immunoinhibitory receptor is part of the cytotoxic T-lymphocyte antigen family.62
Oncoviruses
An estimated 12% of cancers can be caused by an oncovirus, including Epstein–Barr virus (EBV), HPV, human T-cell lymphotropic virus-1 (HTLV-1), Merkel cell polyomavirus (MCPyV), hepatitis B and C viruses (HBV and HCV), and Kaposi sarcoma (KS) herpesvirus (HHV8). As discussed previously, HPV is the most critical oncovirus in the pathogenesis of head and neck cancer and has dramatically changed the demographics and treatment approach as well as outcomes of OPC. HPV-related lesions are increasingly reported at other head and neck sites, including the oral cavity.63 Up to 80% of OPC and 26% of OSCC have been associated with high-risk HPV, showing a continuing trend to increasing HPV in SCC.64 HPV prevalence in the OSCC group was higher than in potentially malignant disorder participants or the control group. The most common HPV subtypes detected in OPC are HPV 16 and 18 (68% and 34%, respectively). Other types of HPV detected in OSCC were HPV 6, 11, 31, 33, 35, and 56.65
EBV and HHV8 are of particular importance to understanding head and neck cancer. EBV infection is noted in malignant transformation of nasopharynx and specific salivary gland cancers. This is discussed further in the section on nasopharyngeal carcinoma. HHV8 or KS herpesvirus, which historically affected older European males, became a global concern during the AIDS epidemic of the 1980s. KS continues to impact immunosuppressed individuals and can occur in the oral cavity. (Figures 7-2 and 7-3).
PRESENTING SIGNS AND SYMPTOMS
Unfortunately, patients are most often identified after the development of symptoms associated with advanced stages of disease. Discomfort is the most common symptom that leads a patient to seek care and may be present at the time of diagnosis in oral cavity tumors. However, oropharynx cancers often present with an awareness of a mass in the neck.66 Dysphagia, odynophagia, otalgia, limited movement, oral bleeding, neck masses, and weight loss may occur with advanced disease.67 Paresthesia or dysesthesia, especially when it is unilateral, is a red flag that may indicate neural involvement and requires that cancer be ruled out. Loss of function involving the tongue can affect speech, swallowing, and diet.
Figure 7‐2 Bilateral involvement of the anterior and posterior hard palate with purple discolorations consistent with Kaposi sarcoma.
Figure 7‐3 Gingival involvement by Kaposi sarcoma, with discoloration and enlargement and soft tissue mass on the maxillary tuberosity.
Possible tissue changes may include a red, white, or mixed red and white lesion; a change in the surface texture producing a smooth, granular, rough, or crusted lesion; or the presence of a mass or ulceration (Figures 7-4, 7-5, 7-6, 7-7, 7-8, and 7-9). The lesion may be flat or elevated and may be minimally palpable or indurated. The high-risk sites for oral carcinoma include the lower lip, the anterior floor of the mouth, and the lateral borders of the tongue.
The clinical presentation may take a different shape in verrucous carcinoma, a subtype of OSCC with characteristic clinical findings. It can be described clinically as grainy, papillary, verruciform, fungating, or cauliflower-like. Verrucous carcinoma may develop from the progression of proliferative verrucous leukoplakia and develop into carcinoma.45,68,69
Figure 7‐4 Irregular erythroleukoplakia of the left lateral border of the tongue.
Lymphatic spread of oral carcinoma most commonly involves the submandibular and digastric nodes and the upper cervical nodes, and can involve the remaining nodes of the cervical chain. The nodes most commonly involved are those that are ipsilateral to the primary tumor, although the closer the tumor is to the midline and the more posterior in the oral cavity or oropharynx, the more common is the involvement of the bilateral and contralateral nodes.
Lymph node involvement may not occur in an orderly fashion. Lymph nodes associated with cancer become enlarged and firm to hard in texture, and with progression may become fixed. The fixation of nodes to adjacent tissue due to invasion of cells through the capsule is a late occurrence and evidence of aggressive disease. The fixation of the primary tumor to adjacent tissue overlying bone suggests the involvement of the periosteum and possible spread to bone. Nodes are not tender unless they are associated with secondary infection or an inflammatory response is present, which may occur after a biopsy. Spread of tumor is critical for prognosis and for selection of treatment. The understaging of nodes by cursory assessment or the overstaging of nodes following a biopsy, when an inflammatory component may be present, impacts the selection of treatment. Therefore, accurate node examination is needed before biopsy.
Figure 7‐5 Previously treated squamous cell carcinomas are at risk of recurrent squamous cell carcinoma. This case was treated with surgery and postoperative radiation therapy and presented with an area of erythroleukoplakia that was diagnosed as recurrent squamous cell carcinoma.
Figure 7‐6 Indurated and ulcerated lesion of the right anterior tongue in a 15-year-old girl, persisting after removal of orthodontic appliances, proven to be squamous cell carcinoma on biopsy.
Figure 7‐7 Nonpainful, irregular indurated exophytic and ulcerated buccal mass; histopathology revealed squamous cell carcinoma.
Figure 7‐8 Eroded, erythroleukoplakic, indurated lesion in the right posterior third of the lateral border of the tongue, diagnosed as squamous cell carcinoma.
It is essential to have an understanding of the differentiation between OSCC and OPC with respect to cervical nodal metastasis. Staging by the AJCC 8th edition (see later) takes into account the high rate of nodal metastasis in HPV-related OPC. Tonsillar and oropharyngeal SCC is more likely to be diagnosed after regional metastasis has occurred, with 12% localized and 67.5% regional metastasis at diagnosis. Metastasis of OSCC at diagnosis is localized in 31.7% or regional in 45.2%. The stage at initial diagnosis is similar across all sexes and ethnic backgrounds for OPC and is related to the molecular behavior of HPV-related tumors, rather than delayed diagnosis or racial or socioeconomic barriers to care.70
DIAGNOSIS AND HISTOPATHOLOGY
Diagnosis is primarily based on histopathology. Within the epithelial tumors, SCC is the most prevalent oral malignancy. It has several subtypes based on histopathology. Some of the variants may have a unique clinical presentation.
For the diagnosis of OSCC, dysplasia involves the full thickness of the epithelium and the basement membrane is violated. Dysplasia describes a range of cellular abnormalities that include changes in cell size and morphology, increased mitotic figures, hyperchromatism, changes in nuclear size and the nuclear–cytoplasmic ratio, and alteration in normal cellular orientation and maturation. Well-differentiated carcinoma retains some anatomic features of epithelial cells, including their ability to produce keratin, whereas poorly differentiated carcinoma involves a loss of the anatomic pattern and function of epithelium. Tumors may be associated with a mixed inflammatory infiltrate. Inflammatory and reactive lesions can be difficult to differentiate from dysplasia, and the experience of the pathologist becomes important with a need for clinical reassessment and repeat investigation. Invasion of lymphatics, blood vessels, and perineural spaces is of critical importance, but is difficult to determine.71
Histologically, verrucous carcinoma is characterized by piling up of keratin on the surface, with downgrowth of club-shaped fingers of hyperplastic epithelium with a pushing front rather than infiltration into the connective tissue. Dysplasia may be mild. Usually, a dense infiltrate of lymphocytes and plasma cells is present. Verrucous carcinoma rarely spreads to lymph nodes and typically remains locally destructive.72,73 The difficulty in diagnosis and treatment is due to a benign histology or mild dysplastic changes that may be seen despite progressive and recurrent disease.
The term basaloid squamous carcinoma (BSC) has been introduced for tumors of which the major portion is composed of a solid growth of basaloid cells with small cystic spaces containing periodic acid–Schiff– and alcian blue–positive material. The histologic hallmark of the neoplasm is that of an OSCC in intimate relationship with a basaloid component. Immunohistochemical findings may be helpful in distinguishing BSC from histopathologically similar tumors.74 HPV-associated cancers of the oral cavity are more likely to have basaloid features.75
Spindle cell carcinoma, also referred to as sarcomatoid SCC, is a rare variant of SCC. The histologic criteria of spindle cell carcinoma is the demonstration of epithelial changes ranging from prominent dysplasia to frank OSCC in conjunction with a dysplastic spindle cell element or evidence of direct transition of epithelial cells to dysplastic spindle cells. Osteoid-appearing material within the spindle cell component can be found.76
A few cases of adenoid SCC of the oral mucosa have been reported, also known as acantholytic SCC. This is mostly seen in the skin and very rarely in the oral cavity. The adenoid structure results from loss of cohesion of the epidermoid tumor cells. It may show pseudovascular morphology.77 Other variants such as carcinoma cuniculatum and intraoral sebaceous carcinoma have been reported and may be confused with more common variants such as mucoepidermoid carcinoma.
While histopathology is the gold standard in diagnosis, it is a subjective assessment of tissue, with inter- and intrarater variability. However, phenotypic changes appear following molecular change, and it is expected that as molecular markers become defined, they will provide additional information and may ultimately become the gold standard in diagnosis.
Staging and Grading of Oral Cancer: Tumor–Nodes–Metastasis System
The American Joint Committee on Cancer (AJCC) Tumor–Nodes–Metastasis (TNM) staging system is the most widely used system for clinical and pathologic staging of cancer. Staging reflects prognosis, and is therefore a determinant of treatment strategy.78 T describes the primary tumor, N indicates the presence of regional lymph node metastasis, and M indicates distant metastasis. The staging system for oral and oropharyngeal cancer combines the T, N, and M categories to classify lesions as stages I through IV and IVA though IVC. The AJCC classification is currently in its 8th edition, which has made significant changes to the TNM staging of head and neck cancers with the aim of improving the reproducible differentiation between stage groups. Major changes from AJCC 7 include newly added staging algorithms for nasopharynx cancer and HPV-mediated oropharynx cancer that reflect the unique biology of these diseases. Changes have also been made to the staging of oral cancer, taking depth of invasion (DOI) and extranodal extension (ENE) into consideration.
There are separate TNM classifications for cancer of the mucosal lip and oral cavity (Table 7-2), HPV-positive and -negative oropharyngeal carcinoma (Table 7-3), and salivary gland carcinomas. The classifications use the same principles with adjustment to the specific anatomic regions.
Adjunctive Diagnostic Aids and Screening Tools
Early detection of potentially malignant and malignant lesions is associated with improved treatment outcomes and a reduction in morbidity of treatment. Patient history and thorough head and neck and intraoral examinations are prerequisites. The definitive test for diagnosis remains tissue biopsy. Several aids to the oral examination were suggested in the past, including light technologies, vital tissue staining using toluidine blue (TB), and computer-assisted cytology of oral brush biopsy specimens.79 Additional markers based on blood and saliva samples are under investigation for use in early detection, diagnosis, and surveillance for recurrence. There is no consensus regarding the standardization of collection, storage, processing, and analysis of salivary biomarkers and this is not currently a feasible clinical tool.80 It is imperative to note that these techniques are adjunctive aids for screening and tools for early detection, and are not a replacement for surgical tissue sample collection and histopathologic diagnosis. The development of noninvasive screening techniques may have impact at the population level with regard to cancer control and detection. Providers implementing these aids in clinical practice should be aware of the utility and limitations of each test in their clinical setting.81
Table 7‐2 Staging of cancer of the mucosal lip and oral cavity.
Reproduced with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al. (Eds.). AJCC Cancer Staging Manual, 8th edn. New York: Springer; 2017: 79–94.
| Primary Tumor (T) | ||
| TX | Primary tumor cannot be assessed | |
| Tis | Carcinoma in situ | |
| T1 | Tumor ≤2 cm with depth of invasion (DOI*) ≤5 mm | |
| T2 | Tumor ≤2 cm with DOI* >5 mm and ≤10 mm; or Tumor >2 cm and ≤4 cm, with DOI* ≤10 mm |
|
| T3 | Tumor >2 cm and ≤4 cm with DOI* >10 mm; or Tumor >4 cm with DOI* ≤10 mm |
|
| T4 | Moderately advanced or very advanced local disease | |
| T4a | Moderately advanced local disease Tumor >4 cm with DOI* > 10mm; or Tumor invades adjacent structures only (e.g., through cortical bone of the mandible or maxilla, or involves the maxillary sinus or skin of the face) NOTE: Superficial erosion of bone/tooth socket (alone) by gingival primary is not sufficient to classify a tumor as T4 |
|
| T4b | Very advanced local disease Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid artery |
|
| *DOI is depth of invasion and not tumor thickness. | ||
| Regional Lymph Nodes (N) | ||
| Clinical N (cN) | Pathological N (pN) | |
| NX | Regional lymph nodes cannot be assessed | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis | No regional lymph node metastasis |
| N1 | Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension, extranodal extension (ENE)(-) | Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension, ENE(-) |
| N2 | Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-); or Metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-); or Metastases in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension, and ENE(-) |
Metastasis in a single ipsilateral node, 3 cm or smaller in greatest dimension and ENE(+); or Larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-); or Metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-); or Metastases in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension, and ENE(-) |
| N2a | Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension, and ENE(-) | Metastasis in single ipsilateral node 3 cm or smaller in greatest dimension and ENE(+); or A single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension, and ENE(-) |
| N2b | Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension, and ENE(-) | Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension, and ENE(-) |
| N2c | Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension, and ENE(-) | Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension, and ENE(-) |
| N3 | Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-); or Metastasis in any node(s) and clinically overt ENE(+) |
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-); or Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or A single contralateral node of any size and ENE(+) |
| N3a | Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-) | Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-) |
| N3b | Metastasis in any node(s) and clinically overt ENE(+) | Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or Multiple ipsilateral, contralateral, or bilateral nodes with any ENE(+); or A single contralateral node of any size and ENE(+) |
| Note: A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(-) or ENE(+). | ||
| Distant Metastasis (M) | ||
| M0 | No distant metastasis | |
| M1 | Distant metastasis | |
| Prognostic Stage Groups | ||
| Stage 0 | Tis N0 M0 | |
| Stage I | T1 N0 M0 | |
| Stage II | T2 N0 M0 | |
| Stage III | T3 N0 M0 | |
| T1 N1 M0 | ||
| T2 N1 M0 | ||
| T3 N1 M0 | ||
| Stage IVA | T4a NO M0 | |
| T4a N1 M0 | ||
| T1 N2 M0 | ||
| T2 N2 M0 | ||
| T3 N2 M0 | ||
| T4a N2 M0 | ||
| Stage IVB | Any T N3 M0 | |
| T4b Any N M0 | ||
| Stage IVC | Any T Any N M1 | |
Table 7‐3 Staging of oropharyngeal cancer.
Source: Reproduced with permission from AJCC: HPV-Mediated (p16+) Oropharyngeal Cancer and Oropharynx (p16-) and Hypopharynx. In Amin MB, Edge SB, Greene FL, et al. (Eds.). AJCC Cancer Staging Manual, 8th edn. New York: Springer; 2017: 113–136.
| Staging of HPV-Mediated (p16+) Oropharyngeal Carcinoma | Staging of Oropharyngeal (p16-) Cancer | |||
| Primary Tumor (T) | ||||
| TX | Primary tumor cannot be assessed | |||
| T0 | No primary identified | |||
| Tis | Carcinoma in situ | |||
| T1 | Tumor 2 cm or smaller in greatest dimension | Tumor 2 cm or smaller in greatest dimension | ||
| T2 | Tumor larger than 2 cm but not larger than 4 cm in greatest dimension | Tumor larger than 2 cm but not larger than 4 cm in greatest dimension | ||
| T3 | Tumor larger than 4 cm in greatest dimension or extension to lingual surface of epiglottis | Tumor larger than 4 cm in greatest dimension or extension to lingual surface of epiglottis | ||
| T4 | Moderately advanced local disease Tumor invades the larynx, extrinsic muscle of the tongue, medial pterygoid, hard palate, or mandible or beyond* |
Moderate advanced or very advanced local disease | ||
| T4a | Moderately advanced local disease Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible* |
|||
| T4b | Very advanced local disease Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base, or encases carotid artery |
|||
| *Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue does not constitute invasion of the larynx | ||||
| Regional Lymph Nodes (N) | ||||
| Clinical N (cN) | Pathological N (pN) | Clinical N (cN) | Pathological N (pN) | |
| NX | Regional lymph nodes cannot be assessed | Regional lymph nodes cannot be assessed | Regional lymph nodes cannot be assessed | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis | No regional lymph node metastasis | No regional lymph node metastasis | No regional lymph node metastasis |
| N1 | One or more ipsilateral lymph nodes, none larger than 6 cm | Metastasis in four or fewer lymph nodes | Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(-) | Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(-) |
| N2 | Contralateral or bilateral lymph nodes, none larger than 6 cm | Metastasis in more than four lymph nodes | Metastasis in a single ipsilateral lymph node larger than 3 cm but not more than 6 cm in greatest dimension and ENE(-); or Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension and ENE(-); or Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension and ENE(-) |
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(+); or Larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-); or Metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-); or Metastases in bilateral or contralateral lymph node(s), none larger than 6 cm in greatest dimension and ENE(-) |
| N2a | Metastasis in a single ipsilateral lymph node larger than 3 cm but not more than 6 cm in greatest dimension and ENE(-) | Metastasis in a single ipsilateral lymph node 3 cm or smaller in greatest dimension and ENE(+); or A single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-) |
||
| N2b | Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(-) | Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(-) | ||
| N2c | Metastases in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-) | Metastases in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-) | ||
| N3 | Lymph node(s) larger than 6 cm | Metastasis in a lymph node more than 6 cm in greatest dimension and ENE(-); or Metastasis in any node(s) and clinically overt ENE(+) |
Metastasis in a lymph node more than 6 cm in greatest dimension and ENE(-); or Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or Multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or A single contralateral node of any size and ENE(+) |
|
| N3a | Metastasis in a lymph node more than 6 cm in greatest dimension and ENE(-) | Metastasis in a lymph node more than 6 cm in greatest dimension and ENE(-) | ||
| N3b | Metastasis in any node(s) and clinically overt ENE(+) | Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or Multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or A single contralateral node of any size and ENE(+) |
||
| Note: A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(-) or ENE(+). | ||||
| Distant Metastasis (M) | ||||
| M0 | No distant metastasis | |||
| M1 | Distant metastasis | |||
| Prognostic Stage Groups | ||||
| Clinical Stage Groups | Pathological Stage Groups | Clinical and Pathological Stage Groups | ||
| Stage 0 | Tis N0 M0 | |||
| Stage I | T0-2 N0-1 M0 | T0-2 N0-1 M0 | T1 N0 M0 | |
| Stage II | T0-2 N2 M0 T3 N0-2 M0 |
T0-2 N2 M0 T3-4 N0-1 M0 |
T2 N0 M0 | |
| Stage III | T0-4 N3 M0 T4 N0-3 M0 |
T3-4 N2 M0 | T3 N0 M0 | |
| T1 N1 M0 | ||||
| T2 N1 M0 | ||||
| T3 N1 M0 | ||||
| Stage IV | Any T Any N M1 | Any T Any N M1 | ||
| Stage IVA | T4a N0 M0 | |||
| T4a N1 M0 | ||||
| T1 N2 M0 | ||||
| T2 N2 M0 | ||||
| T3 N2 M0 | ||||
| T4a N2 M0 | ||||
| Stage IVB | Any T N3 M0 | |||
| T4b Any N M0 | ||||
| Stage IVC | Any T Any N M1 | |||
Vital Tissue Staining with Toluidine Blue
Vital staining with TB may be used as an adjunctive aid in the assessment of potentially malignant oral mucosal lesions. TB is a metachromatic dye that has an affinity to binding with DNA. TB staining has been correlated with LOH profiles in tissue biopsy. TB can be applied directly to suspicious lesions or used as an oral rinse. The assessment of dye uptake depends on clinical judgment and experience (Figure 7-10). Positive retention of TB, particularly in areas of leukoplakia, erythroplakia, and uptake in a peripheral pattern of an ulcer, may indicate the need for biopsy or assist in identifying the site of biopsy. False-positive dye retention may occur in inflammatory and ulcerative lesions, but false-negative retention is uncommon.
Figure 7‐9 Asymptomatic erythroplakia in the floor of the mouth in a patient presenting due to toothache, diagnosed on biopsy as squamous cell carcinoma.
Figure 7‐10 Irregular erythroleukoplakia, following application by toluidine blue. Inferior of lesion and superior stained site were biopsy-proven squamous cell carcinoma.
TB is currently cleared by the US Food and Drug Administration (FDA) as an adjunctive marking aid to a chemiluminescence light device, and not marketed as a stand-alone diagnostic tool. TB has been suggested by the Council on Scientific Affairs of the American Dental Association for use in high-risk patients and high-risk clinical settings by experienced providers, but no guidance was possible for use in the general practice setting due to the lack of clinical study in these settings.82
Visualization Adjunctive Tools
Chemiluminescent devices such as ViziLite® (Den-Mat Holdings, Lompoc, CA, USA) generate light based on chemical reaction. The suspected area of mucosa appears brightly lit. Other products like VELscope® (Apteryx Imaging, Akron, OH, USA) generate fluorescent light using an LED source, sometimes combined with optical filtration of the viewfinder to enhance natural tissue fluorescence. These products are promoted to assist the practitioner in discovering mucosal abnormalities, specifically OPMDs, and to evaluate the margins of a resection site. There is no consensus regarding the sensitivity and specificity of these devices and their ability to detect early disease.
There is an increasing interest in the use of confocal microscopy and optical coherent tomography systems to provide tissue diagnosis in real time, noninvasively, and in situ. Such a diagnostic approach is available in dermatology and is anticipated to be developed for oral mucosal application in the future. Other imaging modalities are being studied due to the need for improved detection and to assist in diagnosis and treatment.83
Cytopathology
Brush cytology, such as the OralCDx® system (OralScan Laboratories, Suffern, NY, USA), combines the cytobrush with a computer-assisted analysis of the cytologic sample, assessing the cell morphology and keratinization. The final diagnosis is made by an examining pathologist on the basis of standard histomorphologic criteria. Further developments in cytology include molecular evaluation of exfoliated cells for molecular markers of dysplasia or carcinoma to improve the diagnostic and prognostic value. Liquid-based cytology has renewed some interest in this noninvasive technique, as it may improve its sensitivity and specificity. This may be combined with biomarkers to improve accuracy, but validated and standardized methods of interpretation have not been established.84
Molecular Analysis
Improved technological advances allow for expeditious and cost-effective molecular analysis of HNSCC tumors and have led to the development and implementation of novel molecular targets for therapeutic suppression and/or enhancement.85 Molecular markers from tissue specimens have elucidated HNSCC HPV-negative and HPV-positive cancers arising from different anatomic locations as well as genomic profiles, molecular characteristics, and therefore clinical prognosis.86 The Cancer Genome Atlas Network (TCGA) and Hammerman et al. (2015) collated the molecular landscape of HPV-positive and HPV-negative HNSCC. HPV-positive tumors often demonstrate mutations in genes E6 and E7, TP53/RB1, TRAF3, FGFR2/3, CD8, DC56, ICOS, LAG3, HLA-DR. Alterations in HPV-negative tumor genes commonly noted were TP53, CDKN2A/RB1, HRAS, CASP8, EGFR, ERBB2, FGF1, FAT1, AJUBA, NOTCH1, TP63, NFE2L2, and KEAP1.87,88
Imaging
Routine radiology, computed tomography (CT), nuclear scintiscanning, magnetic resonance imaging (MRI), and ultrasonography can provide evidence of bone involvement or can indicate the extent of some soft tissue lesions. The selection of the appropriate imaging modality is dependent on the type and location of the suspected tumor. Positron emission therapy (PET) using the radiolabeled glucose analogue 18-fluorodeoxyglucose (18FDG) offers a functional imaging approach for the entire body (Figures 7-11 to 7-17).
Acquisition of a Tissue Specimen
In addition to standard surgical biopsy techniques, tissue can be acquired for histopathology by using fine-needle aspiration (FNA) or core needle biopsy (CNB). Open biopsy of enlarged lymph nodes is not recommended; in such cases, FNA biopsy should be considered. FNA/CNB also may aid in the evaluation of suspicious masses in other areas of the head and neck, including masses that involve the salivary glands, tongue, and palate, or when there is a contraindication to conventional biopsy (e.g., thrombocytopenia). Ultrasound may assist in guiding FNA/CNB.
Treatment
The principal objective of treatment is to cure the patient of cancer with the least possible morbidity of care and maintaining quality of life. The choice of treatment depends upon tumor-specific factors, the site and size of the primary lesion, the presence or absence of metastases, and generalized prognostic data. Current trends in treatment plan recommendations are grounded in fundamentals of patient-centered care, which take into account the patient’s personal preference, current performance status, and ability and willingness to tolerate therapeutic modalities based on cultural, individual, and biopsychosocial-motivated beliefs and attitudes.
Figure 7‐11 Periapical radiograph demonstrating bone destruction in the furcation of the first molar tooth and associated resorption of the root. A subsequent biopsy specimen demonstrated squamous cell carcinoma, which was diagnosed as a primary intra-alveolar lesion.
Stay updated, free dental videos. Join our Telegram channel
VIDEdental - Online dental courses
