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Targeting 
Oral Cancer
Andrew M. Fribley
Editor
123
 Targeting Oral Cancer 
 
 Andrew M. Fribley 
 Editor 
 Targeting Oral Cancer 
 ISBN 978-3-319-27645-8 ISBN 978-3-319-27647-2 (eBook) 
 DOI 10.1007/978-3-319-27647-2 
 Library of Congress Control Number: 2016933453 
 Springer Cham Heidelberg New York Dordrecht London 
 © Springer International Publishing Switzerland 2016 
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 Editor 
 Andrew M. Fribley 
 School of Medicine 
 Wayne State University 
 Detroit , MI 
 USA 
www.springer.com
v
 Part I The Dynamic Epidemiology of Head and Neck 
Cancers and Current Treatment Modalities 
 1 Assessing the Changing Oral and Pharyngeal 
Cancer Demographic in the United States. . . . . . . . . . . . . . . . . 3 
 Andrew S. Holpuch and Susan R. Mallery 
 2 The Emerging Role of HPV in Head 
and Neck Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 
 Thomas E. Carey 
 3 Oral Cancer: Location, Staging, Surgical 
Management, and Outcomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 
 Michael Z. Chen , Robert H. Mathog , 
 Andrew M. Fribley , and George H. Yoo 
 4 Chemotherapy in Head and Neck Squamous 
Cell Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 
 Daniela M. Burchhardt and Ammar Sukari 
 Part II HNSCC: Molecular Progression, Biomarkers 
and Stem Cells 
 5 Molecular Signaling in Oral Cancer Invasion 
and Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 
 Insoon Chang , Aasia O. Rehman , and Cun-Yu Wang 
 6 Cancer Stem Cells in the Biology and Treatment 
of Head and Neck Squamous Cell Carcinoma . . . . . . . . . . . . . 101 
 Hong S. Kim , April Adams , and Jacques E. Nör 
 7 HNSCC Biomarkers Derived from Key Processes 
of Cancerogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 
 Martina Raudenska , Jaromir Gumulec , 
 Andrew M. Fribley , and Michal Masarik 
 Contents 
vi
 Part III Current Trends in Head and Neck Cancer 
Treatment and Novel Therapeutic Approaches 
 8 Emerging Molecular Targets in the Treatment 
of Head and Neck Squamous Cell Carcinoma . . . . . . . . . . . . . 163 
 Blake M. Warner and Jennifer Grandis 
 9 Immunotherapy in Head and Neck Cancers . . . . . . . . . . . . . . . 211 
 Zipei Feng , Carlo B. Bifulco , Rom Leidner , 
 R. Bryan Bell , and Bernard A. Fox 
 10 The Unfolded Protein Response as a Therapeutic 
Target for Head and Neck Squamous Cell Carcinoma . . . . . . 225 
 Danielle M. Garshott , Shelby A. Bechler , 
 Daniela M. Burchhardt , Priyanka Shah O’Brien, 
 George H. Yoo, Daniel J. Chiego Jr., Aasia O. Rehman, 
Michael U. Callaghan, and Andrew M. Fribley 
 11 Targeting Coagulation Mediators in Head 
and Neck Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 
 Rohith Jesudas , Qinghua Zeng , Danielle M. Garshott , 
 Nicholas Yoo , Andrew M. Fribley , Jordan A. Shavit , 
and Michael U. Callaghan 
 12 Mucosal Therapy for Potentially Malignant 
Diseases and OSCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 
 Peter F. Svider , Blake M. Warner , Scott J. Schwartz , 
 Danielle M. Garshott , James D. Weinstein , 
and Andrew M. Fribley 
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 
Contents
vii
 April Adams , BS Department of Cariology, Restorative Sciences, 
Endodontics , University of Michigan School of Dentistry , 
 Ann Arbor , MI , USA 
 Shelby A. Bechler , BS, MS Fribley-Callaghan Collaboratory , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 R. Bryan Bell , MD, DDS, FACS Department of Surgery , 
 Providence Portland Medical Center, Providence Cancer Center, 
Robert W. Franz Cancer Research, Earle A. Chiles Research Institute , 
 Portland , OR , USA 
 Carlo B. Bifulco , MD Providence Portland Regional Laboratory , 
 Portland , OR , USA 
 Department of Translational Molecular Pathology , 
 Robert W. Franz Research Center, Earle A. Chiles Research Institute, 
Providence Cancer Center, Providence Portland Medical Center , 
 Portland , OR , USA 
 Daniela M. Burchhardt , BA, MD Department of Otolaryngology, 
Head and Neck Surgery , Wayne State University School of Medicine , 
 Detroit , MI , USA 
 Fribley-Callaghan Collaboratory , Wayne State University School of Medicine , 
 Detroit , MI , USA 
 Karmanos Cancer Institute , Detroit , MI , USA 
 Michael U. Callaghan , MD Fribley-Callaghan Collaboratory , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 Division of Hematology Oncology, Carman and Ann Adams 
Department of Pediatrics , Wayne State University School of Medicine , 
 Detroit , MI , USA 
 Thomas E. Carey , PhD Department of Otolaryngology/Head Neck Surgery , 
 The University of Michigan Health System , Ann Arbor , MI , USA 
 Insoon Chang , DDS, MS Division of Oral Biology & Medicine , 
 UCLA School of Dentistry , Los Angeles , CA , USA 
 Contributors 
viii
 Michael Z. Chen , MD Department of Otolaryngology, 
Head and Neck Surgery , Wayne State University School of Medicine , 
 Detroit , MI , USA 
 Karmanos Cancer Institute , Detroit , MI , USA 
 Daniel J. Chiego Jr. , BA, MS, PhD Department of Cariology , Restorative 
Sciences and Endodontics, University of Michigan School of Dentistry , 
 Ann Arbor , MI , USA 
 Fribley-Callaghan Collaboratory , Wayne State University School of Medicine , 
 Detroit , MI , USA 
 Zipei Feng , BS, MD, PhD Robert W. Franz Cancer Research Center, 
Earle A. Chiles Research Institute, Providence Cancer Center, 
Providence Portland Medical Center , Portland , OR , USA 
 Departmentsof Cancer Biology , Oregon Health and Science University , 
 Portland , OR , USA 
 Bernard A. Fox , PhD Robert W. Franz Cancer Research Center, 
Earle A. Chiles Research Institute, Providence Cancer Center, 
Providence Portland Medical Center , Portland , OR , USA 
 Department of Molecular Microbiology and Immunology , 
 Oregon Health and Science University , Portland , OR , USA 
 UbiVac , Portland , OR , USA 
 Andrew M. Fribley , PhD Fribley-Callaghan Collaboratory , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 Division of Hematology Oncology, Carman and Ann Adams 
Department of Pediatrics , Wayne State University School of Medicine , 
 Detroit , MI , USA 
 Karmanos Cancer Institute , Detroit , MI , USA 
 Department of Otolaryngology, Head and Neck Surgery , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 Molecular Therapeutics Group , Karmanos Cancer Institute , 
 Detroit , MI , USA 
 Danielle M. Garshott , BS Fribley-Callaghan Collaboratory , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 Carman and Ann Adams Department of Pediatrics , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 Jennifer Grandis , MD Department of Otolaryngology, 
Head and Neck Surgery , Clinical and Translational Science Institute, 
University of California, San Francisco , San Francisco , CA , USA 
 Jaromir Gumulec , MD Department of Pathological Physiology, 
Faculty of Medicine , Masaryk University , Brno , Czech Republic 
Contributors
ix
 Andrew S. Holpuch , DDS, PhD Department of Oral and Maxillofacial 
Pathology and Radiology, The Ohio State University , Columbus , OH , USA 
 Rohith Jesudas , MD Fribley-Callaghan Collaboratory , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 Division of Hematology Oncology, Carman and Ann Adams 
Department of Pediatrics , Wayne State University School of Medicine , 
 Detroit , MI , USA 
 Hong S. Kim , BS Department of Cariology, Restorative Sciences, 
Endodontics , University of Michigan School of Dentistry , 
 Ann Arbor , MI , USA 
 Rom Leidner , MD Providence Oral, Head and Neck Cancer Program, 
Providence Portland Medical Center, Providence Cancer Center, 
Robert W. Franz Research Cancer Center, Earle A. Chiles Research Institute , 
 Portland , OR , USA 
 Susan R. Mallery , DDS, PhD Department of Oral and Maxillofacial 
Pathology and Radiology , The Ohio State University Medical Center (Joint 
Appointment), The Ohio State University , Columbus , OH , USA 
 Michal Masarik , PhD Department of Pathological Physiology, 
Faculty of Medicine , Masaryk University , Brno , Czech Republic 
 Jacques E. Nör , DDS, MS, PhD Department of Cariology, 
Restorative Sciences, Endodontics , University of Michigan School of Dentistry , 
 Ann Arbor , MI , USA 
 Department of Biomedical Engineering , University of Michigan 
College of Engineering , Ann Arbor , MI , USA 
 Department of Otolaryngology , University of Michigan School of Medicine , 
 Ann Arbor , MI , USA 
 University of Michigan Comprehensive Cancer Center , 
 Ann Arbor , MI , USA 
 Priyanka Shah O’Brien , MD Fribley-Callaghan Collaboratory , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 Department of Otolaryngology, Head and Neck Surgery , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 Karmanos Cancer Institute , Detroit , MI , USA 
 Martina Raudenska , PhD Department of Pathological Physiology, 
Faculty of Medicine , Masaryk University , Brno , Czech Republic 
 Aasia O. Rehman , PhD Department of Pediatrics and Communicable 
Diseases , University of Michigan Medical School , Ann Arbor , MI , USA 
 Scott J. Schwartz , MD Fribley-Callaghan Collaboratory, Wayne State 
University School of Medicine , Detroit , MI , USA 
Contributors
x
 Jordan A. Shavit , MD Department of Pediatrics and Communicable 
Diseases , University of Michigan School of Medicine , Ann Arbor , MI , USA 
 Department of Pediatrics , CS Mott Children’s Hospital, 
University of Michigan , Ann Arbor , MI , USA 
 Ammar Sukari , MD Department of Otolaryngology, Head and Neck 
Surgery , Wayne State University School of Medicine , Detroit , MI , USA 
 Karmanos Cancer Institute , Detroit , MI , USA 
 Peter Svider , MD Department of Otolaryngology, Head and Neck Surgery , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 Karmanos Cancer Institute , Detroit , MI , USA 
 Cun-Yu Wang , DDS, PhD Division of Oral Biology and Medicine , 
 UCLA School of Dentistry , Los Angeles , CA , USA 
 Blake M. Warner , DDS, PhD, MPH Division of Oral and Maxillofacial 
Pathology, Department of Diagnostic Sciences , University of Pittsburgh, 
School of Dental Medicine , Pittsburgh , PA , USA 
 James Weinstein , MD Professor of Neuroscience, Marshall University 
School of Medicine (Retired) , Bridgeport , WV , USA 
 George H. Yoo , MD Department of Otolaryngology , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 Karmanos Cancer Institute , Detroit , MI , USA 
 Nicholas Yoo Fribley-Callaghan Collaboratory , Wayne State University 
School of Medicine , Detroit , MI , USA 
 Qinghua Zeng , PhD, MD Fribley-Callaghan Collaboratory , 
 Wayne State University School of Medicine , Detroit , MI , USA 
 Division of Hematology Oncology, Carman and Ann Adams Department 
of Pediatrics , Wayne State University School of Medicine , 
 Detroit , MI , USA 
Contributors
 Part I 
 The Dynamic Epidemiology of Head 
and Neck Cancers and Current 
Treatment Modalities 
 
3© Springer International Publishing Switzerland 2016 
A. Fribley (ed.), Targeting Oral Cancer, DOI 10.1007/978-3-319-27647-2_1
 Assessing the Changing Oral 
and Pharyngeal Cancer 
Demographic in the United States 
 Andrew S. Holpuch and Susan R. Mallery 
 Abstract 
 In 2015, oral and pharyngeal cancer (OPC) will be diagnosed in an estimated 
45,780 people in the United States (71.3 % male – accounting for 4 % of all 
cancer diagnoses in men) and 8650 deaths (69.4 % male) will be attributed 
to this disease. While the 5-year survival rate has slowly improved over the 
last several decades, mirroring an overall decline in tobacco use, the inci-
dence has increased largely due to a rise in human papillomavirus (HPV)-
associated oral and pharyngeal cancers. These primary risk factors (i.e., 
tobacco use and HPV infection), along with alcohol consumption, dietary 
patterns, immunosuppression, and genetic predisposition, are introduced 
relative to their role in the development of OPC. Concepts for the detection 
(clinical tools and appearance of precancerous lesions) and prevention 
(behavioral modifi cation and HPV vaccination) of OPC are also presented. 
1.1 Epidemiology 
and Demographics 
 In 2015, it is estimated that 1.65 million 
Americans will be diagnosed with cancer (51.1 % 
male) and nearly 600,000 will succumb to the 
disease (52.9 % male) [ 1 ]. As a result of changing 
behavioral trends and improved preventative 
screening, the collective incidence of all cancers 
has continued to decline over the past twodecades 
[ 1 ]. Similarly, 5-year relative survival rates have 
improved nearly 20 % since 1975 [ 1 ]. While 
these general trends portray overall improvement 
in the incidence and management of cancer in the 
United States, evaluation of race- and location- 
specifi c statistics demonstrates unique trends 
relative to individual cancer types. 
 Specifi cally, in 2015, oral and pharyngeal can-
cer (OPC) will be diagnosed in an estimated 
45,780 patients in the United States (71.3 % 
male – accounting for 4 % of all cancer diagnoses 
in men) and 8650 deaths (69.4 % male) will be 
attributed to this disease [ 1 ]. As defi ned by the 
 A. S. Holpuch , DDS, PhD 
 Department of Oral and Maxillofacial Pathology 
and Radiology , The Ohio State University, 
 Columbus , OH , USA 
 e-mail: holpuch.5@osu.edu 
 S. R. Mallery , DDS, PhD (*)
 Department of Oral and Maxillofacial Pathology 
and Radiology , The Ohio State University Medical 
Center (Joint Appointment), The Ohio State 
University, Columbus , OH , USA 
 e-mail: Mallery.1@osu.edu 
 1
mailto:holpuch.5@osu.edu
mailto:Mallery.1@osu.edu
4
International Classifi cation of Diseases, Tenth 
Division (ICD-10), OPC is classifi ed as any 
malignant neoplasm of the lip, oral cavity (tongue, 
major salivary glands, mucosa, fl oor of mouth, 
other/unspecifi ed parts of oral cavity), and phar-
ynx (oropharynx, nasopharynx, and hypopharynx) 
[ 2 ]. Clearly, the broad classifi cation of OPC 
encompasses a multitude of cancer subtypes, but 
roughly 90 % of these are represented by squa-
mous cell carcinoma (SCC) [ 3 ]. Although the 
overall 5-year survival rates for OPC have signifi -
cantly increased from 53 % in 1975 to 66 % in 
2010 – a number likely skewed due to increased 
detection and prevention of lip cancers – disparity 
among racial survival rates is evident (Caucasian: 
67 %; African-American: 45 %) [ 1 ]. This dispar-
ity has been attributed to lack of early detection, 
as 27 % of African- Americans have distant metas-
tases at the time of diagnosis compared to only 
16 % of Caucasians, i.e., the greatest disparity of 
all cancers presented by Siegel et al. [ 1 ]. Not sur-
prisingly, 5-year relative survival rates vary with 
the stage at diagnosis: 79 % survival with local-
ized disease, 42 % for regional disease and 19 % 
for distant metastases [ 4 ]. 
 Access to high-quality healthcare due to an 
inequitable poverty burden is a major contributing 
factor to these disparities, as even in Medicare-
insured patients, African-Americans are less 
likely to receive standard-of-care therapies than 
their corresponding Caucasian patients [ 5 , 6 ]. 
Notably, patients diagnosed with late-stage OPC 
were also more likely to be uninsured or Medicaid 
recipients (OR: 1.37, 95 % CI 1.21–1.25) [ 7 ]. 
 Interestingly, despite improved statistics 
regarding overall OPC incidence and mortality, a 
trend reversal has been observed in certain demo-
graphic groups [ 8 ]. While analysis of the National 
Cancer Institute’s Surveillance, Epidemiology, 
and End Results (SEER) data over the past four 
decades (i.e., data currently available from 1975 to 
2011) provides similar OPC data to that presented 
above (i.e., generalized improvement of observed 
incidence rates for all genders and races: Caucasian 
males, −1.21 %; Caucasian females, −0.66 %; 
African-American males, −1.53 %; African-
American females, −1.38 %), temporal stratifi ca-
tion of the data over the past 5 years shows that the 
greatest decline was observed in African-American 
males (−6.64 %) while the incidence in African-
American females actually increased from −1.38 
to +3.18 % [ 8 ]. Interestingly, mortality rates for 
Caucasian males have increased more rapidly over 
the last 10 years (30 years, −2.16 %; 10 years, 
−1.83 %; 5 years, −0.33 %) [ 8 ]. 
 These trends were further clarifi ed when bro-
ken down by geographic distribution, which 
showed increased mortality rates across all races 
in eight states (Nevada, North Carolina, Iowa, 
Ohio, Maine, Idaho, North Dakota, and 
Wyoming) [ 8 ]. Notably, within the last 5 years, 
Nevada, Idaho, and North Dakota showed marked 
increases in mortality rates in Caucasian males 
over the age of 50 [ 8 ]. Evaluation of the most 
recent Behavioral Risk Factor Surveillance 
System (BRFSS) data shows that fi ve of the eight 
states identifi ed with increased OPC mortality 
rates also had higher than average rates of alcohol 
and tobacco consumption patterns, i.e., primary 
risk factors for OPC [ 8 ]. While there appears to 
be a correlation with alcohol and tobacco use and 
oral cancer mortality rates, Kentucky and 
Wisconsin have the highest levels of current 
tobacco and alcohol consumers, but demonstrate 
decreasing rates of oral cancer incidence and 
mortality [ 8 ]. This indicates that other risk fac-
tors are involved in the development and progres-
sion of OPC in the United States (Table 1.1 ).
 Not surprisingly, in addition to the African- 
American/Caucasian disparities revealed from 
the analysis of the SEER and BRFSS data, there 
are also substantial differences for OPC inci-
dence in other ethnic groups. Nasopharyngeal 
cancers (NPC) are elevated in Chinese immi-
grants from the Szechuan province [ 9 ]. 
Interestingly, nasopharyngeal cancer rates from 
Szechuan province immigrants are intermediate 
between US-born Chinese and those persons who 
remain in the Szechuan province, fi ndings which 
imply a combination of both genetic and environ-
mental factors in the pathogenesis of this disease 
[ 9 ]. NPCs are also unique from standard oropha-
ryngeal squamous cell carcinomas via the well- 
recognized contribution of Epstein–Barr virus 
and the accompanying heavy lymphocytic infi l-
trate [ 10 ]. As additional SEER and BRFSS data 
are compiled, disparities in the incidence and 
mortality in diverse ethnic groups are expected. 
A.S. Holpuch and S.R. Mallery
5
 Furthermore, the previous studies did not 
characterize demographic changes with regard to 
cancer type or location (e.g., oral SCC or 
 pharyngeal SCC – i.e., as separate entities). 
Stratifying the data by tumor location shows an 
increase in pharyngeal cancers in Caucasian 
males, without concomitant increases in oral cav-
ity cancers [ 11 ]. These changing trends within 
this specifi c demographic group have been asso-
ciated with an increasing prevalence of human 
papillomavirus infections in the oropharynx [ 11 ]. 
These data highlight the importance of demo-
graphic-specifi c risk factors, of which additional 
studies investigating race- and geographic-related 
differences in OPC incidence and mortality could 
provide valuable insight for the education and 
prevention in specifi c populations. 
1.2 Risk Factors 
 Identifying and understanding the contributing 
factors to the development of OPC will facili-
tate the detection and prevention of disease. 
Numerous behavioral and physical factors are 
associated with the development of OPC and, 
more specifi cally, oral and pharyngeal squa-
mous cell carcinoma. Age is frequently consid-
ered a risk factor for OPC, as it historically 
occurs in persons over the age of 40, indicating 
a temporal component for the accumulation of 
cellular damage resulting in malignant transfor-
mation potential. In spite of the contribution of 
age to cancer development, a paradigm shift in 
OPC development is actively underway with 
increasing incidence of OPCs in nonsmokers 
under the age of 60 and in nontraditional ana-
tomical locations [ 11 ]. 
 Cancers of the anterior oral cavity (i.e., ante-
rior of tonsillar pillars) are most commonly asso-
ciated with alcohol and tobacco use, which are 
routinely monitored on the state level by the 
Centers for Disease Control’s Offi ce on Smoking 
and Health via the National Health Interview 
Survey (NHIS) and Behavioral Risk Factor 
Surveillance System (BRFSS). These surveys 
provide valuable data regarding use patterns, but 
do not establishassociations between these pat-
terns and cancer incidence. Furthermore, alcohol 
and tobacco use in the United States have 
decreased over the past several decades, but race 
and location-specifi c trends have developed [ 8 ]. 
These changes in the demographic affected by 
OPC are likely due to shifting risk behaviors and 
new, emerging risk factors. Specifi cally, the 
human papillomavirus serotypes 16 and 18 (i.e., 
high-risk oncogenic HPV16 and HPV18) are 
directly responsible for the increasing incidence 
of pharyngeal cancers in Caucasian males under 
the age of 60 [ 11 , 12 ]. In addition to these promi-
nent risk factors, dietary habits, sun/ultraviolet 
exposure (lip cancers), betel quid use (common 
in Eastern countries), immunosuppression, and 
genetic predisposition are all considered risk fac-
tors for the development of oral and pharyngeal 
squamous cell carcinoma. 
1.2.1 Tobacco and Alcohol 
 The development of OPC is linked to numerous 
risk factors, representing a multifaceted etiology, 
 Table 1.1 Risk factors associated with the development of OSCC 
 Risk factor Unique features of associated tumor 
 Tobacco OSCCs retain many molecular characteristics of tobacco- induced malignancies at other 
sites such as lung; features that likely refl ect the robust carcinogen metabolism present 
in human oral epithelia 
 Alcohol 
 Human papillomavirus More sensitive to selective chemotherapeutics and radiation; multimodal treatment has 
achieved higher success rates for this OSCC variant 
 Diet 
 Immune status If iatrogenic immunosuppression, tumor immunity will improve with reduction/
elimination of immunosuppressant drugs 
 Heritable conditions With the specifi c molecular mutations and defi ciencies identifi ed, targeted therapy to 
address these issues is now feasible 
1 Assessing the Changing Oral and Pharyngeal Cancer Demographic in the United States
6
with tobacco and alcohol consumption generally 
considered the primary risk factors. Over the last 
several decades, the US government has causally 
linked tobacco use to the development of cancer 
at eight major anatomical sites, and it is related to 
increased mortality in several others [ 13 ]. While 
other risk factors play a role in OPC etiology, his-
torically, tobacco represents the most important, 
yet preventable cause of OPC. 
 The majority of tobacco-related carcinogens 
are by-products of pyrolysis, of which over 4000 
chemical constituents are produced [ 13 ]. 
Smokeless tobacco varies widely based on the 
production process but favors the formation of 
carcinogenic tobacco-specifi c N-nitrosamines 
[ 14 – 19 ]. In addition, studies have shown interpa-
tient heterogeneity with regard to an individual’s 
capacity to bioactivate carcinogens present in 
smokeless tobacco (e.g., N′-nitrosonornicotine 
and 4-(methylnitrosamino)-1-3-pyridyl-1-buta-
none) [ 16 – 20 ]. More specifi cally, the presence of 
phase I and II metabolic enzymes within the oral 
epithelium predisposes the individual to the pro-
duction of carcinogens from compounds present 
in smokeless tobacco [ 20 , 21 ]. Burnt tobacco 
releases an additional group of chemicals, i.e., 
the polycyclic aromatic hydrocarbons. The fate 
of these chemicals in the mouth is also contingent 
upon the smoker’s oral epithelial metabolic pro-
fi le [ 22 , 23 ]. Cytochrome p450 enzymes 1A1, 
1B1, and 1A2 which are present in human oral 
epithelia can bioactivate benzo(a)pyrene to the 
ultimate carcinogen benzo(a)pyrene diol epoxide 
[ 22 ]. Persons with a preponderance of phase II 
enzymes, such as GSH-s-transferases and UGT 
glucuronosyl transferases that are also present in 
human oral epithelia, have greater inherent pro-
tective potential [ 24 ]. These enzymes convert the 
reactive oxygenated polycyclic aromatic hydro-
carbons to more polar compounds for excretion 
in the urine [ 23 , 24 ]. Collectively, these data 
demonstrate the carcinogenic potential of both 
smokeless and smoked tobacco products (i.e., 
cigarettes, pipe, and cigars), with a greater predi-
lection toward smoked tobacco by-products and 
OPC. In addition, during concurrent alcohol and 
tobacco use, alcohol acts as a solvent for tobacco 
carcinogens, enhances their penetration through 
the surface epithelium, and enables access to critical 
oral epithelial stem cell populations [ 25 , 26 ]. 
 While numerous studies have established 
tobacco use and alcohol consumption as indepen-
dent risk factors (i.e., increasing risk for OPC by 
up to 27-fold), combined use results in synergis-
tic development of OPC [ 7 ]. A recent study 
(2004) evaluating 137 cases of OPC demon-
strated a synergistic effect of tobacco and alcohol 
use [ 27 ]. The authors identifi ed the multivariate 
odds ratios (OR) for developing OPC in heavy 
smokers (OR: 20.7), heavy drinkers (OR: 4.9), 
and combined use (OR: 48) [ 27 ]. A similar study 
separated risk by anatomical site, showing syner-
gistically elevated risk of OPC development in 
the oral cavity (OR: 228) and/or pharynx (OR: 
100) in individuals consuming more than 77 
drinks per week and smoking more than 25 ciga-
rettes per day [ 28 ]. Interestingly, increased alco-
hol consumption with stable tobacco use 
correlated with an increase of oral cavity, but not 
pharyngeal, cancer development [ 28 ]. Finally, a 
large case–control study (1114 OPC cases and 
1268 controls) in the United States found similar 
synergism between tobacco and alcohol con-
sumption (estimating that combined use accounts 
for roughly 75 % of OPC in the United States), 
with those individuals smoking more than 2 
packs and consuming more than 4 drinks per day 
increasing their odds 35-fold for developing OPC 
[ 29 ]. Taken together, these studies demonstrate 
the substantial role of tobacco and alcohol use in 
the development of OPC. 
1.2.2 Oncogenic Strains of Human 
Papillomavirus 
 The human papillomavirus, principally HPV 
subtypes 16 and 18, has been defi nitively associ-
ated with the development of OPC, particularly 
in the oropharynx, base of tongue, tonsillar pil-
lars, and tonsils [ 12 ]. HPV is a common, sexually 
transmitted virus, with over 100 serotypes, which 
have infected an estimated 40 million Americans 
[ 11 , 12 ]. While most Americans will be exposed 
to HPV in their lifetimes, by either oncogenic or 
non-oncogenic serotypes, an estimated 1 % lacks 
A.S. Holpuch and S.R. Mallery
7
the immune response to HPV16, resulting in an 
increased risk of developing OPC [ 11 , 12 ]. Over 
the past several decades, changing sexual behav-
iors in young adults are increasing the spread of 
HPV and, thus, resulting in a pronounced increase 
of OPC incidence in the younger demographic 
without prominent alcohol/tobacco histories [ 30 , 
 31 ]. These sexual behaviors include young age at 
fi rst intercourse, history of genital warts, and 
number of sexual partners (greater than 26 for 
vaginal sex and greater than 6 for oral sex – indi-
cating that oral sex is strongly associated with a 
risk of HPV infection and OPC development) 
[ 31 , 32 ]. Other prominent factors associated with 
HPV infection include the male sex, husbands of 
females with a history of cervical carcinoma, a 
history of sexually transmitted diseases, human 
immunodefi ciency virus infection, and immuno-
suppression [ 31 – 34 ]. 
 In 1985, Löning et al. identifi ed a causal rela-
tionship between HPV and OPC [ 35 ]. Since this 
discovery, the link between high-risk HPV sub-
type 16 and OPC has been elucidated (both 
molecularly and epidemiologically) as a signifi -
cant etiological factor, accounting for up to a 
15-fold increase in the development of OPC [ 36 –
 38 ]. Unfortunately, HPV-positive OPCs often 
present at an advanced stage (i.e., cervical lymph 
node involvement), but unlike OPCs associated 
with traditional risk factors, HPV-positive OPCs 
are seemingly more sensitive to chemoradiother-
apy resulting in improved progression-free sur-
vival rates (approximately 70% greater than 
non-HPV OPC survival rates) [ 39 – 42 ]. 
Interestingly, studies in patients with OPC have 
shown a 15-fold increase of HPV-positive can-
cers in nonsmokers than smokers [ 41 ]. 
Collectively, these results demonstrate HPV as a 
distinct risk factor for OPC, which is shifting 
toward a younger demographic. 
1.2.3 Dietary 
 Dietary factors, and a generally healthy lifestyle, 
play a signifi cant role in decreasing the risk of 
preventing numerous cancer types, including 
OPC. The scientifi c evidence, however, does not 
provide the defi nitive association that has been 
shown with tobacco/alcohol and HPV, which is 
likely attributed to confounding variables with 
regard to lifestyle that diminish dietary 
associations. 
 Several studies have investigated vitamin 
intake relative to OPC risk; demonstrating diets 
low in beta-carotene, vitamin C, vitamin D, and 
vitamin E increased the risk of developing OPC, 
while diets high in these factors imparted a pro-
tective effect by reducing risk by nearly 50 % 
[ 43 – 49 ]. Specifi cally, vitamin C consumption 
greater than 745 mg/week exhibited a protective 
effect in two separate studies, decreasing risk of 
developing OPC with odds ratios of 0.39 and 
0.63 [ 43 , 50 ]. Similarly, regular use of vitamin D 
and E supplements reduced OPC risk to 0.76 and 
0.5, respectively [ 46 , 51 ]. In general, studies 
evaluating vegetable and fruit consumption have 
shown a protective effect against OPC [ 52 – 54 ]. 
In contrast, a case–control study in Uruguay with 
4000 participants demonstrated that diets high in 
red meat signifi cantly increased the odds of 
developing OPC (OR: 3.65) [ 55 ]. In general, 
these studies demonstrate that diets high in veg-
etable and fruit consumption exhibit a protective 
effect, while the converse enhance OPC risk. 
1.2.4 Immunosuppression 
 Immunocompromised patients are at high-risk 
for several forms of cancer, including OPC. This 
group includes those infected with human immu-
nodefi ciency virus (HIV) and those recipients of 
iatrogenic immunosuppression (e.g., transplant 
recipients). 
 While HIV-positive patients are at an increased 
risk of developing oral and pharyngeal SCCs 
(OR: 1.4–2.6 relative to non-HIV population in 
the United States), they are also historically 
prone to the development of Kaposi’s sarcoma 
and non-Hodgkin’s lymphoma within the oral 
cavity [ 56 , 57 ]. Studies evaluating SEER data 
from the 1980s, coinciding with the HIV epi-
demic in the United States, demonstrated a 
14-fold increase of oral Kaposi’s sarcoma and 
non-Hodgkin’s lymphoma in 20–54-year-old 
1 Assessing the Changing Oral and Pharyngeal Cancer Demographic in the United States
8
males in the San Francisco, California (high- 
density of HIV positive patients), area relative to 
other SEER combined sites [ 58 ]. In addition, 
recent studies suggest that up to 26 % of HIV- 
infected individuals are coinfected with the onco-
genic HPV16, compared to roughly 1 % of the 
non-HIV population [ 59 ]. The increased inci-
dence of HPV infection combined with the high 
prevalence of tobacco use in the HIV-positive 
population is expected to result in the increased 
incidence of OPC in the near future [ 59 ]. 
 Prolonged iatrogenic immunosuppression, 
such as that following hematopoietic stem cell 
transplantation (HSCT), can be complicated by 
the development of chronic graft versus host 
 disease (cGVHD) and the subsequent increased 
risk of developing solid tumors, including 
OPC. Common immunosuppression regimens 
include combination treatment with cyclospo-
rine, tacrolimus, azathioprine, and corticoste-
roids [ 60 ]. In 1997, Curtis et al. conducted a 
multi-institute database study of 19,229 patients 
who had received HSCT and concluded that the 
male sex, cGVHD, and greater than 24-month 
treatment with azathioprine were strongly linked 
to an increased risk of developing OPC 
(OR: 11.1) [ 60 , 61 ]. Specifi cally, a combination 
of cyclosporine, azathioprine, and corticosteroids 
resulted in a fi vefold increased risk of developing 
OPC [ 60 ]. Collectively, immunosuppressed indi-
viduals and those with a history of HSCT or 
cGVHD are at an elevated risk for developing 
OPC and require periodic, thorough oral 
evaluations. 
1.3 Heritable Conditions 
Associated with the 
Development of OSCC 
 While efforts to elucidate a “genetic fi ngerprint” 
indicative of the development of oral squamous 
cell carcinoma (OSCC) have not yet been suc-
cessful, inroads into genetic and epigenetic con-
tributing factors have been made. Identifi cation 
that loss of heterozygosity at specifi c tumor sup-
pressor loci heralds malignant transformation of 
premalignant oral epithelial lesions enhanced the 
predictability of OSCC development [ 62 ]. 
Furthermore, demonstration of the extensive het-
erogeneity of human oral cavity xenobiotic- 
metabolizing enzymes provides insights 
regarding the varied sensitivities of human oral 
mucosal epithelia to recognized carcinogens [ 20 –
 22 , 24 ]. The integral role of genetics in OSCC 
development, however, is most clearly manifest 
by two heritable conditions, i.e., Fanconi anemia 
(FA) and dyskeratosis congenita (DC). Both of 
these conditions are associated with a dramati-
cally higher risk (1000-fold) and at a younger age 
for OSCC development [ 63 , 64 ]. While the spe-
cifi c genetic perturbations of FA and DC are 
unique, there are also striking similarities 
between these diseases [ 63 , 64 ]. Both FA and DC 
belong to the “inherited bone marrow failure syn-
dromes” that include other heritable diseases 
such as Diamond–Blackfan anemia and severe 
congenital neutropenia [ 64 ]. Although all of 
these heritable syndromes carry an increased risk 
for acute myeloid leukemia, FA and DC are 
uniquely also susceptible to solid cancers [ 65 , 
 66 ]. Marked chromosomal instability – attribut-
able to faulty DNA repair (FA) and telomerase 
function (DC) – is a predominant common fea-
ture of FA and DC [ 65 , 66 ]. Furthermore, both 
FA and DC patients experience immunosuppres-
sion attributable to bone marrow suppression, 
which enhances their tumor susceptibility [ 67 , 
 68 ]. A fi nal commonality is the nature of the tis-
sues that undergo malignant transformation [ 63 , 
 64 ]. Both FA and DC cancers arise in tissues with 
rapid cell turnover that mandates high replication 
rates such as bone marrow and throughout the 
gastrointestinal track (predominantly oral cavity) 
and skin [ 63 , 64 ]. (Please see Table 1.2 for a 
 summary of clinical and genetic features.) 
A recently published science article substantiates 
these clinical observations. This study employed 
a rigorous mathematical model to compare the 
estimated number of stem cell divisions at a tis-
sue site with cancer risk [ 69 ]. Similar to these 
clinical observations in FA and DC patients, the 
authors concluded that tissues with higher rates 
of stem cell divisions experienced higher cancer 
incidence [ 69 ]. The longevity of stem cells – 
including mutated stem cells – and their potential 
A.S. Holpuch and S.R. Mallery
9
to pass these mutations to daughter cells were an 
underlying premise for their observations [ 69 ].
1.3.1 Fanconi Anemia 
 FA is a rare (approximately 1 in 200,000–400,000 
live births) heritable condition that exhibits both 
autosomal recessive (majority ~98 %) and 
X-linked patterns of inheritance [ 70 , 71 ]. 
Sophisticated genetic analyses have revealed up 
to 15 unique “complementation groups” or 
genetic subtypes in FA: FA-A, FA-B, FA-C, 
FA-D1, FA-D2, FA-E, FA-F, FA-G, FA-I, FA-J, 
FA-L, FA-M, FA-N, FA-O, and FA-P [ 72 – 74 ]. In 
2002 Howlett et al. discovered that FANCD1 is 
 BRCA2 and determined that mono-allelic muta-
tions resulted in breast cancer whereas bi-allelic 
mutations were associated with FA [ 75 ]. Despite 
the diversity of genetic subtypes, chromosomal 
 Table 1.2 Features, genetic mutations, and associated diseases inpersons with Fanconi anemia and dyskeratosis 
congenita 
 Clinical manifestations 
 Fanconi anemia Developmental defects that can include short stature, cardiac and renal abnormalities, 
endocrinopathies, hyperpigmentation 
 Most consequential: bone marrow failure or aplastic anemia at a young age 
 Dyskeratosis congenita “Classic triad” which consists of dystrophic nail changes, oral leukoplakia, reticulated 
skin pigmentation. May also note pulmonary fi brosis, hypogonadism, alopecia, cirrhosis, 
canities prematura 
 Most consequential: bone marrow failure at a young age 
 Patterns of inheritance 
 Fanconi anemia Autosomal recessive (majority) 
 X-linked (1–2 %) 
 Dyskeratosis congenita Autosomal dominant 
 X-linked 
 Diagnostic criteria 
 Fanconi anemia Chromosomal instability and sensitivity to cross-linking agents. Positive results not 
pathognomonic as may refl ect other syndromes associated with unstable DNA 
 Conclusive tests entail screening for mutation in the known FA genes (15 distinct 
“complementation groups” recognized) 
 Dyskeratosis congenita Genetic analyses reveal mutations in gene that codes for telomerase RNA (autosomal 
dominant), mutations in DKC1 (X-linked) 
 Genetic mutations 
 Fanconi anemia Genes affected: FANCA, CANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, 
FANCF, GANCG, FANCJ (BRIP1), FANCL, FANCM/Hef 
 FANC proteins function in a myriad of roles in DNA repair that include formation of a 
nuclear complex necessary for ubiquitination and others that support endonuclease and 
helicase functions. FA proteins associate with other DNA repair complexes 
 Dyskeratosis congenita Genes affected: DKC1 (X-linked, codes for the telomerase RNA- associated protein 
dyskerin ), hTR (autosomal dominant, gene that codes for human telomerase RNA), 
 NOLA3 (autosomal recessive, telomerase maintenance) 
 The associated genetic mutations cause telomerase erosion and defi ciency, which 
ultimately result in chromatin instability 
 Cancer risk 
 Fanconi anemia Acute myeloid leukemia (may be preceded by myelodysplastic syndrome) 
 Head and neck squamous cell carcinoma (HNSCC) 
 Esophageal carcinomas 
 Genitourinary cancers in women 
 Dyskeratosis congenita Acute myeloid leukemia 
 Head and neck squamous cell carcinoma . May experience multiple primary tumors. If 
multiple tumors, HNSCC almost always present 
 Skin and gastrointestinal carcinomas, Hodgkin’s and non-Hodgkin’s lymphoma 
1 Assessing the Changing Oral and Pharyngeal Cancer Demographic in the United States
10
instability is the hallmark feature of all FA com-
plementation groups. In health, FA proteins form 
multi-protein nuclear complexes that collectively 
form the FA pathway [ 76 ]. Healthy FA proteins 
perform a variety of roles in DNA repair includ-
ing homologous recombination and contribute to 
ubiquitin ligase function [ 63 ]. Of note, FA pro-
teins also interact in a cooperative fashion with 
other DNA repair pathways [ 63 ]. In addition, a 
role for FA proteins in monitoring oxidative 
stress and initiating protective responses has been 
identifi ed [ 77 ]. Provided the oral cavity’s high 
levels of exposure to xenobiotics, infl ammation, 
and associated reactive species, the need for 
timely cytoprotective responses to reduce reac-
tive oxygen species-mediated genetic damage is 
readily apparent. 
 While development of aplastic anemia between 
the ages of 5 and 10 is the most common FA pre-
sentation, FA-attributable developmental anoma-
lies such as small stature could prompt an earlier 
diagnosis [ 63 ]. The “chromosomal breakage test,” 
which entails challenge of suspected FA patients’ 
peripheral blood lymphocytes with DNA clasto-
genic agents, remains the most common test to 
evaluate for FA [ 78 ]. Formerly, FA chromosomal 
fragility was formerly attributed exclusively to FA 
cells’ loss of “caretaking genes” needed for DNA 
repair. A retrospective analysis, however, that ques-
tioned which evolutionary pressures might man-
date protection from completely man-made 
reagents, has revised this assessment [ 79 ]. The 
evolved concept combines reduced DNA repair 
capacity with susceptibility to the redox stress that 
arises from metabolism of DNA interstrand cross-
linking agents [ 79 ]. These authors have concluded 
that a prooxidant state exists in at least three FA 
subtypes, A, C, and G [ 79 ]. Other investigators 
have confi rmed mitochondrial dysfunction and 
impaired ROS degradation [ 80 ]. Provided the 
oncogenic potential of reactive species-mediated 
nuclear and mitochondrial and DNA damage and 
inappropriately sustained intracellular signaling, 
the prooxidant cancer-permissive phenotype is 
understandable [ 81 ]. 
 As a result of early diagnosis, successes of 
allogenic bone marrow transplantations, and 
improvements in graft versus host management, 
many FA patients now live into adulthood [ 82 ]. 
This enhanced life span – combined with the 
inherent cancer susceptibility – has redirected the 
focus to early detection and management of solid 
tumors [ 82 ]. While only 6 % of all worldwide 
malignancies are head and neck squamous cell 
carcinomas (HNSCC), HNSCCs represent the 
predominant solid cancers found in FA patients 
[ 83 ]. Approximately 50 % of nontransplanted FA 
patients will develop HNSCC by age 45 while 
100 % of FA transplant recipients will develop 
HNSCC by 45 [ 84 ]. Furthermore while the 
majority of FA head and neck squamous cell car-
cinomas occur in the oral cavity, about 33 % 
develop in non-visibly detectable sites including 
oropharynx, nasopharynx, and larynx, which cre-
ate challenges for early detection [ 85 ]. 
 The etiology of FA OSCCs is distinct from 
the general population. While tobacco and alco-
hol use are the primary initiators of OSCC, FA 
patients’ tumors most frequently arise in very 
young patients with negative social histories 
[ 86 ]. Oncogenic human papillomavirus (HPV) 
subtypes have more recent been implicated in 
some FA OSCCs [ 83 ]. Oncogenic HPV infec-
tion initiates the FA pathway in normal epithelial 
cells while genomic instability becomes accen-
tuated in FA keratinocytes [ 83 ]. Furthermore, 
the absence of an intact FA pathway increases 
the susceptibility of FA cells to oncogenic HPV 
infections [ 83 ]. Notably, confl icting data regard-
ing the contribution of oncogenic HPV in FA 
OSCCs has arisen from the European (HPV 
absence) and US (HPV presence) FA patient 
cohorts [ 83 , 85 ]. Evaluations of US patients’ 
FA OSCC tumors demonstrated the presence of 
oncogenic HPV in 84 % (21 of 25 tumors) evalu-
ated [ 85 ]. In contrast European FA OSCCs did 
not reveal any high-risk HPV subtypes [ 24 ]. As 
both studies employed comparable HPV detec-
tion methodology, these clinical differences 
were thought to refl ect geographic variations in 
the prevalence of HPV infections [ 83 , 85 ]. The 
European studies also assessed surrogate HPV 
markers, i.e., elevation of p16, p53 silencing as 
a result of HPV E6 protein, and evaluated p53 
mutations [ 83 ]. Interestingly, the data revealed 
that non-HPV-containing FA OSCC tumors 
A.S. Holpuch and S.R. Mallery
11
 demonstrated comparable TP53 allelic losses as 
seen in sporadic OSCCs [ 83 ]. Current guidelines 
for FA patients recommend close clinical follow-
up, with oral cavity evaluations to be conducted 
by a health professional every 3 months begin-
ning at 10 years of age [ 83 ]. 
1.3.2 Dyskeratosis Congenita 
 As previously mentioned dyskeratosis congenita 
(DC) and FA are unique among the bone marrow 
failure syndromes by virtue of their increased sus-
ceptibility to solid tumors. Like FA, DC is also 
heritable by an X-linked recessive pattern, an auto-
somal recessive pattern, and unlike FA also an 
autosomal dominant pattern of inheritance [ 64 ]. In 
addition, sporadic cases, presumed to refl ect domi-
nant de novo gene mutations, are also fairly fre-
quent [ 66 ]. The incidence of solid cancer 
susceptibility in DCpatients is only surpassed by 
persons with FA [ 64 ]. Comparable to FA, the 
majority of DC patients with multiple tumors 
develop at least one HNSCC [ 64 ]. The actuarial 
cancer risk for persons with DC is ~40 % by age 
50 and over 60 % by age 68 [ 64 ]. DC, like FA, is a 
rare condition, with a prevalence of approximately 
1 in 1,000,000 births [ 66 ]. While bone marrow 
failure may be the presenting manifestation, early 
in life persons with DC often develop “dyskera-
totic” features that entail dystrophic nails, reticular 
skin pigmentation, and precancerous oral epithe-
lial lesions [ 66 , 87 ]. A diagnosis of DC can be 
made of the basis of two of three of the “diagnostic 
triad” [ 66 ]. In addition, clinical presentations of 
DC can vary in accordance with the extent of 
expression, a feature that is most notable in patients 
with the autosomal dominant form [ 64 ]. 
 The underlying defi cit in DC patients’ cells is 
defective telomerase activity [ 66 ]. The specifi c 
proteins affected, however, are unique depending 
upon the inheritance patterns [ 66 ]. The DKC1 
gene, which is responsible for production of dys-
kerin, is mutated in persons with X-linked DC [ 64 ]. 
Major functions of dyskerin include RNA process-
ing, conversion of rRNA uridine residues to pseu-
douridine, and maintenance of the telomerase 
enzyme complex through RNA binding [ 64 – 66 ]. 
Nonfunctional dyskerin has appreciable conse-
quences, most notably faulty telomerase function 
and premature telomere shortening [ 64 ]. Similarly, 
autosomal dominant DC also perturbs telomerase 
function via mutations in the telomerase RNA 
component [ 64 ]. The genetic perturbation that 
occurs in autosomal DC was elusive and more 
recently identifi ed as a homozygous mutation in 
 NOLA3 (also known as NOP10 ), which also func-
tions in telomere maintenance [ 88 ]. Many cancers 
“preserve” cellular life spans by increasing telo-
mere length. DC’s premature telomerase shorten-
ing that is accompanied by a cancer-promoting 
phenotype is somewhat paradoxical. Telomere ero-
sion and instabilities are permissive for end-to-end 
chromosomal fusion, a feature that could dramati-
cally perturb cell replenishment [ 89 ]. Healthy 
human oral epithelia self-renew approximately 
every 28 days. The dramatic predilection for oral 
cancers in DC likely refl ects the telomerase depen-
dency of tissues that require constant cell turnover 
and the cancer-enabling consequences of growth- 
promoting chromosomal fusions [ 64 ]. 
 Management strategies for persons with DC 
are complicated by the varying degrees of disease 
expression and the specifi c tissues affected [ 66 ]. 
Unlike FA, bone marrow transplantation has not 
uniformly increased survival in persons with DC 
[ 64 ]. Alternate therapies such as anabolic steroids 
with reduced androgenizing effects and selective 
bone marrow donors and recipients, i.e., siblings 
for patients with no existing pulmonary disease, 
have proven more successful. With regard to 
patients’ oral lesions, the current recommenda-
tions include monthly self- examinations and 
three evaluations by healthcare professionals a 
year (two with the patient’s dentist, one with an 
otolaryngologist) [ 66 ]. 
1.4 Detection 
 Factors affecting incidence would presumably 
also affect mortality rates; however, some factors 
(e.g., stage at diagnosis, access to care, and treat-
ment success) infl uence mortality but not 
 incidence. Since 1973, the SEER data have not 
shown any improvement in the proportion of 
1 Assessing the Changing Oral and Pharyngeal Cancer Demographic in the United States
12
OPCs diagnosed at earlier stages (i.e., more 
localized). This suggests a failure by healthcare 
professionals to screen for lesions at early stages, 
a lack of effective screening methods, or lack of 
patient access to screening exams. 
 Precursor lesions for OSCC frequently present 
clinically as white (leukoplakia), red (erythropla-
kia), or mixed (erythroleukoplakia) well-defi ned 
lesions [ 90 ]. These lesions are commonly found 
in “pooling areas” of the oral cavity, such as the 
fl oor of mouth, ventrolateral tongue, and retromo-
lar trigone where carcinogen-laden saliva bathes 
the local mucosa. With the exception of erythro-
plakia (lesions severe dysplasia or worse – micro-
scopically), clinical presentation of a lesion does 
not convey the extent of maturational disturbances 
that range from relatively benign (atypia) to 
intraepithelial cancer (carcinoma in situ). In addi-
tion, as premalignant oral epithelial lesions are 
dynamic, clinical appearances can vary to 
extremely subtle to readily visible in a matter of 
days [ 91 ]. This phenotype can complicate early 
diagnosis for even experienced clinicians. 
 The oral epithelium is composed of several 
layers of keratinocytes, but in normal epithelium, 
only the deepest layer adjacent to the basement 
membrane (i.e., stratum basale) undergoes cell 
division to repopulate the superfi cial layers (i.e., 
stratum spinosum, granulosum, and corneum). In 
oral dysplasia and carcinoma in situ, however, 
this homeostatic process is disrupted and the 
aberrant keratinocytes inappropriately replicate 
DNA and proliferate throughout the full- 
thickness epithelium. Studies have shown that up 
to 36 % of histologically confi rmed premalignant 
lesions transform to overt OSCC, acquiring the 
capacity to invade the basement membrane and 
metastasize to distant sites [ 92 ]. Also, prolifera-
tive verrucous leukoplakia represents a unique 
spectrum of changes that entail multifocal oral 
premalignant lesions that have a markedly ele-
vated propensity (over 70 %) of undergoing 
malignant transformation [ 93 ]. 
 Currently, the two best predictive indicators 
that an oral epithelial dysplastic lesion will prog-
ress to OSCC are lesional histologic grade and loss 
of heterozygosity (LOH) at putative tumor sup-
pressor gene loci [ 94 , 95 ]. Once the basement 
membrane has been violated by tumor cells, both 
lesional microscopic appearance (histologic 
grade) and extent of disease [clinical extent staged 
per standard T (size of primary tumor), M (present 
of distant disease), N (lymph node involvement) 
protocol] are employed to determine the overall 
prognosis and optimal treatment strategy [ 90 ]. 
 As alluded to above, a host of logical biomark-
ers to predict malignant transformation potential, 
e.g., chromosomal polysomy, loss of E-cadherin 
accompanied by nuclear translocation of beta- 
catenin, and aberrant p 53 expression, have been 
helpful [ 92 , 96 ]. To date, only microscopic appear-
ance and LOH have shown predictive benefi t [ 92 , 
 95 , 96 ]. Due to the vast intra-tumor and interpa-
tient heterogeneity of protein expression and sig-
naling profi les in OSCC, a collective panel of 
numerous biomarkers is likely a more viable 
option for routine histopathological screening of 
potential disease progression to invasive OSCC. 
 Field cancerization is a theory in which one or 
more areas of epithelium, including the transient 
amplifying population and epithelial stem cells, 
have acquired pro-tumorigenic genetic modifi ca-
tions (e.g., loss of tumor suppressor genes) [ 97 ]. A 
fi eld lesion does not demonstrate invasion of the 
basement membrane, a trademark of overt carci-
noma; however the accumulation of genetic aber-
rations in cell progeny leads to progressive 
pro-tumorigenic traits (e.g., uncontrolled prolifer-
ation and invasion) [ 97 ]. Aspects of the recognized 
high-risk disease proliferative verrucous leukopla-
kia are an excellent clinical example of multifocal 
oral epithelial “initiation.” This concept presents a 
challenge for patient management as excision of 
an entire lesion with clean microscopic margins 
will inevitably leave “fi eld cancerized” epithelium 
behind leading to local recurrence. 
1.5 Strategies to Enhance 
Detection of Premalignant 
and Early Malignant Oral 
Epithelial Lesions 
 While thorough examinationby well-trained 
clinicians employing good lighting remains an 
effective means for early detection of most 
A.S. Holpuch and S.R. Mallery
13
 premalignant lesions and early OSCCs [ 98 ], a 
variety of adjunct detection methods have been 
developed. One of the fi rst methods to be devel-
oped and thoroughly investigated was vital tis-
sue staining via application of the metachromatic 
dye, toluidine blue, to high-risk sites to facili-
tate in the detection of suspicious oral lesions 
[ 99 – 101 ]. As toluidine blue stains nuclear and 
mitochondrial DNA, its use was logical, espe-
cially for the identifi cation of high-grade dys-
plasia and early malignant disease that has an 
abundance of cells with hyperdiploid nuclei 
[ 102 ]. These studies demonstrate the benefi ts of 
toluidine blue application by well-trained clini-
cians for the identifi cation of suspicious lesions 
and selection of biopsy sites. Generalized tolu-
idine blue application by less experienced 
healthcare providers, however, is not recom-
mended. Instead, patients should be referred to 
a head and neck specialist for more extensive 
assessment. 
 While benefi cial, toluidine blue has not 
proven to be a useful diagnostic aid for most 
nonspecialized clinicians. To fi ll this void, a 
variety of commercial products have entered the 
oral diagnosis fi eld. One of the best-recognized 
commercialized ventures was OralCDX, distrib-
uted by OralCDx Laboratories Suffern, NY. The 
OralCDx kit includes a stiff brush, which is used 
by the clinician to obtain a cytological prepara-
tion that should, if performed correctly, include 
the all- important basal layer keratinocytes. The 
 submitted cytological preparation is then 
assessed via computer analyses for a variety of 
features including cytomorphometry, DNA 
cytometry, and selected immunocytochemical 
parameters [ 103 ]. This technology that was mar-
keted to general dental practitioners as a “brush 
biopsy” unfortunately has a fatal fl aw, i.e., false 
negatives [ 104 ]. False positives lead to addi-
tional costs, e.g., blade biopsy and pathology 
fees and anxiety for patients. False negatives, 
however, provide a deceptive sense of security 
and enable signifi cant lesions such as OSCCs to 
escape detection and treatment. This signifi cant 
issue has reduced confi dence in the usefulness of 
OralCDx for identifi cation of premalignant and 
early malignant disease. 
 A variety of spectroscopy-based devices, 
which employ fl uorescent, light scattering, and 
Raman spectroscopic techniques, to facilitate 
detection of preneoplastic and early OSCC 
have also been developed [ 105 ]. The underly-
ing basis for all these technologies is predicated 
upon “unique spectral patterns” that are created 
as oral epithelia transitions from health to a pre-
neoplastic–neoplastic state [ 105 ]. Some of the 
most aggressively marketed techniques entailed 
used of a fl uorescent light-emitting source, e.g., 
VELscope (Visually Enhanced Lesion Scope, 
LED Dental, White Rock, British Columbia) 
and Vizilite (DenMat, Lompoc, CA). While con-
ceptually feasible, this technology has encoun-
tered several challenges that have restricted its 
applicability. As presented by the manufactur-
ers, fl uorescence attenuation, i.e., quenching, 
correlates with premalignant or malignant epi-
thelial changes. In addition, the manufacturers 
acknowledged a variety of clinical confounders 
such as physiologic pigmentation that would 
perturb interpretation. More extensive confound-
ing factors that attenuated fl uorescence includ-
ing a large spectrum of nonneoplastic conditions 
as chronic mucositis, common variations of nor-
mal, e.g., geographic tongue, traumatic ulcer-
ation, lymphoid aggregates, and physiologic 
melanin pigmentation were identifi ed in an IRB-
approved VELscope study (Fig. 1.1 ) [ 106 ]. In 
addition, certain healthy anatomical sites, i.e., 
attached gingiva and tonsillar pillars, also func-
tioned as effective “fl uorescence quenchers” 
[ 106 ]. More issues were encountered with vary-
ing degrees of fl uorescence attenuation that com-
plicated interpretation regarding whether or not 
the loss of fl uorescence was adequate to deem 
the lesion “suspicious” [ 106 ]. Collectively, these 
extensive confounding variables, reported inci-
dents of false-negative fi ndings, increased cost 
and stress to patients who receive false-positive 
imaging, and cost of the equipment – coupled 
with the concern that clinicians may rely exten-
sively on fl uorescence technology and overlook 
premalignant or malignant lesions – have mark-
edly reduced enthusiasm for use of fl uorescent 
spectroscopy for reliable diagnosis of preneo-
plastic and neoplastic oral lesions [ 107 ].
1 Assessing the Changing Oral and Pharyngeal Cancer Demographic in the United States
14
1.6 Risk Reduction Strategies 
 Efforts to prevent the development of OPC 
involve a combined approach of early detection, 
behavior modifi cation, and therapeutic interven-
tion and require active participation from both 
the patient and clinician. As discussed above, 
early detection, monitoring, and surgical man-
agement via blade excision or laser ablation of 
premalignant lesions represent the primary meth-
ods of OPC prevention and management. In addi-
tion, tobacco cessation programs and the advent 
of readily available oncogenic HPV vaccinations 
provide preventive avenues for minimizing the 
risk associated with OPC development. 
 Tobacco use is the leading cause of prevent-
able diseases worldwide; not surprisingly, tobacco 
and alcohol cessation programs also represent the 
primary behavioral modifi cation for preventing 
OPCs. Studies have demonstrated that tobacco 
cessation is currently the most effective means 
of inducing stable, long-term regression and 
decreases the risk of developing second primary 
cancers in OSCC survivors [ 108 , 109 ]. Efforts to 
prevent tobacco and alcohol use in adolescents are 
optimal, as individuals lacking a smoking/alcohol 
history have a signifi cantly reduced risk of devel-
oping OPC and other diseases. Community- and 
state-based initiatives include the enforcement of 
advertising and sales restrictions and promotion 
of abstinence from tobacco/alcohol use through 
school-based programs. For those individuals 
who have tobacco- use histories, cessation advice 
provided by physicians, dentists, and other pri-
mary care personnel (i.e., offi ce-based cessation 
programs) can signifi cantly impact decisions 
regarding tobacco discontinuation. The National 
Cancer Institute (NCI) has published two manu-
als specifi cally designed to guide the physician or 
dentist through the advising process of tobacco 
cessation [ 110 , 111 ]. In addition to these manu-
als, the NCI has also published a summary of the 
effectiveness and obstacles encountered through 
offi ce-based cessation programs [ 112 ]. On a larger 
scale, hospital- based programs funded by the NCI, 
the American Lung Association, the CDC, and 
most notably the National Tobacco Prevention and 
Control Program’s Initiatives to Mobilize for the 
Prevention and Control of Tobacco Use (IMPACT) 
are also available for community- based cessation. 
 In addition to tobacco-related prevention of 
OPCs, HPV-positive OPCs are optimal candidates 
a b
 Fig. 1.1 ( a ) The clinical photograph (left image) depicts 
an ulcerated lesion with indurated borders of the left lat-
eral–ventral tongue. The biopsied specimen was micro-
scopically diagnosed as moderately differentiated 
squamous cell carcinoma. ( b ) The right photograph dem-
onstrates its corresponding VELscope image. A focus of 
bright orange fl uorescence, consistent with bacterial colo-
nization of portions of the ulcer’s fi brinous pseudomem-
brane, is apparent. The squamous cell carcinoma 
demonstrates a loss of fl uorescence relative to the uniform 
apple-green birefringence of the surrounding normal tis-
sues. Fluorescence reduction, however, is not uniform 
throughoutthe specimen. Notably, only a portion of the 
carcinoma demonstrates complete fl uorescence quench-
ing (Clinical photograph and VELscope image compli-
ments of Dr. Kristin McNamara, Division of Oral 
Maxillofacial Pathology and Radiology, College of 
Dentistry, the Ohio State University) 
 
A.S. Holpuch and S.R. Mallery
15
for targeted prevention as they continue to increase 
in prevalence [ 113 , 114 ]. Two US Food and Drug 
Administration-approved vaccines are currently 
available (i.e., HPV bivalent, types 16 and 18; and 
HPV quadrivalent, types 6, 11, 16, and 18) and have 
been shown to be highly effective at preventing 
HPV-related cancers [ 115 – 117 ]. While evidence 
showing that vaccination protects against HPV-
positive OPCs has yet to be established (several 
clinical trials are currently underway), herd immu-
nity to the oncogenic HPV subtypes is expected to 
decrease the incidence of HPV-positive OPC [ 114 ]. 
Unfortunately, recent data from 2012 show that 
only 53.8 % girls and 6.8 % of boys ages 13–17 had 
received the full course of HPV vaccinations, of 
which vaccination must be done prior to fi rst sexual 
intercourse to prevent possible infection [ 114 ]. 
Furthermore, carriers of oral HPV can be identifi ed 
and educated regarding their individual risk of pro-
gression to OPC and the risk of infecting others. 
1.7 Summary 
 The oral and pharyngeal cancer demographic has 
been shifting toward male Caucasians under the 
age of 60. This shift is the result of increasing 
oncogenic HPV infections in the oral cavity, 
resulting in the development of OPC. Additionally, 
the common risk factors, i.e., alcohol/tobacco 
and poor diet, still remain as prominent contribu-
tors to the progression of oral and pharyngeal 
cancers. Efforts to detect these lesions at an early 
stage through screenings provided by healthcare 
professionals (i.e., with or without diagnostic 
aids) prevent their development (HPV vaccina-
tion) or progression (surgical/pharmacologic 
management, tobacco cessation, diet modifi ca-
tion) and are anticipated to curtail the rising rate 
of cancers in the oral cavity and pharynx. 
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