Oral Oncology 49 (2013) 10971102Contents lists available at ScienceDirect

Oral Oncology

journal homepage: www.elsevier .com/locate /ora loncologyReviewHead and neck squamous cell carcinoma in young patients1368-8375/$ - see front matter 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.oraloncology.2013.09.001

Corresponding author. Tel.: +31 626708260; fax: +31 71 526 5930.E-mail addresses: h.s.van_monsjou@lumc.nl (H.S. van Monsjou), wrees-

mav@mskcc.org (V.B. Wreesmann), m.vd.brekel@nki.nl (M.W.M. van den Brekel),a.balm@nki.nl (A.J.M. Balm).

1 Tel.: +1 212 639 2000.2 Tel.: +31 20 512 2550; fax: +31 20 512 2554.Hester S. van Monsjou a,, Volkert B. Wreesmann b,1, Michiel W.M. van den Brekel c,2, Alfons J.M. Balm c,2aDepartment of Otorhinolaryngology, Leiden Medical Center, PO Box 9600, 2300 RC Leiden, The NetherlandsbHead and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USAcDepartment of Head and Neck Surgery and Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

a r t i c l e i n f o s u m m a r yArticle history:Received 11 June 2012Received in revised form 16 May 2013Accepted 2 September 2013Available online 6 October 2013

Keywords:Head and neckSquamous cell carcinomaYoungHPVIncidenceRisk factorsEpidemiologic analyses have shown disproportional increases of head and neck squamous cell carcinoma(HNSCC) incidence in a younger age group (younger than 45 years old), compared to patients above45 years old. Although this group is small (5%), it includes a significant subset of the HNSCC patient pop-ulation, and is characterized by a distinct clinical and etiological phenotype. HNSCC in young patientsoften presents without significant exposure to alcohol and tobacco and primarily affects the oropharynxand oral cavity. Exposure to human papilloma virus (HPV) has been identified as a major contributor tothe pathogenesis of oropharyngeal carcinomas, and explains part of the observed incidence variation.Specific hereditary influences, including genetic predispositions accounting for an increased mutagensensibility and inherited syndromes like Fanconi Anemia and Blooms syndrome, have been identifiedas causative factors in a subgroup of young-onset HNSCC, but their cumulative influence remains at pres-ent likely underestimated. Circumstantial evidence suggests that young-onset HNSCC patients have aclinically different phenotype compared to older patients, however, the true impact of young age onHNSCC clinical behavior will remain difficult to determine unless multi-institutional databases will becombined. The rising incidence of youngonset HNSCC mandates intensification of research endeavorsinto its etiology, clinical phenotype and optimal management.

2013 Elsevier Ltd. All rights reserved.Introduction

Cancer results from cellular acquisition of genetic changes thatpromote malignant behavior. Accordingly, it often occurs in thecontext of increased exposure to (extrinsic) DNA damaging factors,and/or decreased function of intrinsic DNA protection factors. Headand neck squamous cell carcinoma (HNSCC) includes a spectrum ofmucosa-derived tumors along the upper aerodigestive tract andconstitutes a classic example of this phenomenon. On the one handof the spectrum, HNSCCs develop after significant and long lastingexposure to tobacco and alcohol. These patients account for5070% of all HNSCCs and are typically males in their 6th7th dec-ade of life. On the other hand, the HNSCC spectrum contains asmall but significant subset of patients (5%), who develop HNSCCat a young age (2540 years old), without significant exposure toalcohol and tobacco. This disparity suggests that the pathogenesisof head and neck cancer in young patients differs from head andneck cancer development in old patients, which may berepresented by the presence of clinically relevant differences inincidence, etiologic factors, clinical behavior, and outcomebetween young and old patients with HNSCC. The present reviewdescribes these differences and focuses on possible clinicalconsequences.Incidence

HNSCC includes tumors arising in the oral cavity, oropharynx,larynx and hypopharynx, and is the 6th most common cancerworldwide. The estimated annual global burden of HNSCC isapproximately 560,000 incident cases and approximately 300,000resultant deaths. The overall incidence of HNSCC varies consider-ably throughout the world with incidence peaks in Southeast Asia,parts of Central and southwest Europe (Spain, France) and Brazil,and low incidence figures in Japan, China and West Africa. NorthAmerica and Northern Europe occupy an intermediate position inthis spectrum [1,2]. The geographical incidence variation is gener-ally explained by inherited factors and a parallel variation ofcarcinogen exposure intensity across the globe. In addition to geo-graphic variation, the incidence of HNSCC has been characterizedby significant temporal variation over the last 50 years. Overallincidence rates show a declining trend in both sexes in India, HongKong, Brazil and US whites, and an increasing trend is observed in

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1098 H.S. van Monsjou et al. / Oral Oncology 49 (2013) 10971102most other populations, particularly in Central and Eastern Europe,Scandinavia, Canada, Japan and Australia [38].

The true global HNSCC incidence in young patients is unknownbecause most epidemiologic studies do not report HNSCCincidence data stratified by age. Estimates of HNSCC incidencefrom some reports suggest that 6.7% of HNSCC patients are youn-ger than 45 years, and 0.43.6% of patients are younger than40 years [912]. For areas like Southeast Asia and India, where highHNSCC incidences are reported, proportional high incidences foryoung patients are reported as well, and temporal variation isproportional to that of adult HNSCC [1315]. In the Western worldhowever, including Europe and the United States, several recentreports suggest increasing incidence trends of HNSCC in youngpatients, disproportional to HNSCC patients above 45 years old (Ta-ble 1) [1620]. Within this subgroup of young onset HNSCC thedistribution of males and females is different. Whereas the oldergroup shows men accounting for approximately 70% of cases, inyounger HNSCC patients men account for 5065%. Moreover, themajority of young non-smoking non-drinking HNSCC patients isfemale [21].

It is noteworthy that the HNSCC increase in young patients isprimarily due to increased incidence of oropharyngeal and oralcavity squamous cell carcinomas among this population. For exam-ple, Shiboski et al. noted carcinoma of the tonsil, tongue and baseof tongue increasing in young white patients from 1973 to 2001in the US [19], and a Scandinavian study noted an increase of 56-fold in tongue carcinoma under the age of 40, compared to a2-fold increase in the HNSCC population above 40 year old [16].An overview of the recent literature on studies reporting inci-dences of young HNSCC patients is presented in Table 1. Althoughthe incidence of young-onset HNSCC varies significantly betweencountries in the Western World [22], a nearly uniform rise is no-ticed in oral cavity and oropharyngeal SCC [23]. On the contrary,laryngeal and hypopharyngeal SCCs in young patients are rare, ac-count for approximately 10% and 1% of all HNSCCs in patients aged

H.S. van Monsjou et al. / Oral Oncology 49 (2013) 10971102 1099ing rates with 49.8% in 1979, 32.5% in 1990, 21.1% in 1995, and18.8% in 1996. The Global Status Report Alcohol and young peo-ple reports that young people are starting to drink at earlier ages[37]. The prevalence of drinking alcohol in secondary school chil-dren in the UK, declined from 25% in 2003 to 23% in 2004. This fig-ure had previously increased over time from 20% in 1988 to 27% in1996, and has since fluctuated within this range, showing no clearpattern over recent years. Thus, regular alcohol intake in Westernyouth is decreasing while heavy consumption of alcohol over ashort period of time (binge drinking) has become more popularin recent years.

The increased incidence of oral and oropharyngeal carcinomasin a setting of decreasing tobacco and alcohol exposure, andagainst a background of stable low rates of classically tobacco-re-lated laryngeal and alcohol-related hypopharyngeal carcinomassuggests that this increase at most is minimally related to changesin alcohol/tobacco exposure. Before definitive conclusions aboutthe role of tobacco and alcohol exposure and young-onset HNSCCcan be drawn, the sensitivity of the young upper aerodigestivetract to these compounds needs better definition. For example,although the lag-time between tobacco/alcohol exposure initiationand HNSCC development in young patients may be short comparedto classical lag-time estimates in older HNSCC patients [38], theexistence of intrinsic sensitivity factors in young HNSCC patientsmay amplify the oncogenic effect of these mutagens. This is furthersuggested by the disproportional number of cases without anyknown risk factor [18,39] for HNSCC development among theyoung population and suggests that factors other than tobaccoand alcohol are implicated when HNSCC is developed at a youngage.Extrinsic risk factors: HPV

Human papilloma virus is transmitted by sexual intercourseand causes 95% of cervical squamous cell carcinomas. In recentyears, HPV has also been identified as a major contributor to thepathogenesis of oropharyngeal carcinomas, but not oral, laryngealand hypopharyngeal SCCs [28]. Molecular, epidemiological andclinical evidence implicates HPV in oropharyngeal SCC develop-ment and progression. HPV DNA is present in oropharyngeal tumorcells either integrated into host DNA or present in cytoplasmicepisomes. Evidence of functionally active HPV can be found inthe majority of these cells, including the presence of viral mRNAand proteins [40]. Oncogenic properties have been attributed tothe HPV E6 and E7 proteins, which confer the high risk HPVphenotype, through disruption of key tumorsuppresor genesincluding p53 (degraded by E6) and Rb (degraded by E7), amongseveral others.

In contrast to HPV-negative OPSCC, HPV-positive OPSCC ischaracterized by absence of p53 mutations and nearly uniformoverexpression of p16 (resultant from decreased negative feedbackby Rb) [41]. HPV-positive OPSCCs also appear to be associatedwith a distinct clinical profile from HPV-negative OPSCC. The clin-ical behavior of HPV-positive oropharyngeal SCCs in terms of re-sponse to treatment and prognosis, is clearly superior comparedto HPV-negative OPSCCs [42]. The higher survival rate among pa-tients with HPV-positive SCC is due in part to greater locoregionalcontrol, reflecting higher intrinsic sensitivity to radiation or betterradiosensitization by Cisplatin-based chemoradiation strategies[43]. Finally, HPV-positive OPSCC is characterized by significantlylower rates of self-reported tobacco/alcohol exposure, andsignificantly higher rates of self-reported sexual promiscuity andmarijuana use. The association between marijuana use andHPV-16 positive HNSCC needs further research. It is currently un-known whether smoking of marijuana is an epiphenomenon of apromiscuous lifestyle, or actively promotes HPV induced carcino-genesis through its immunosuppressive potential [44]. Altogether,the epidemiology of HPV explains a significant part of the in-creased incidence of young-onset OPSCC.Intrinsic risk factors

A fourth contributor to young-onset HSNCC includes geneticpredisposition. Hereditary influences on development of HNSCCare most dramatically exemplified by patiens challenged by oneof several well-defined inherited HNSCC-susceptibility syndromes(Table 2) For example, patients with the autosomal dominant Li-Fraumeni syndrome, inherited bone marrow failure syndromesincluding autosomal recessive Fanconi anemia (FA) and Bloomssyndrome as well as autosomal dominant Dyskeratosis congenitafeature a dramatic increased incidence of squamous cell carcinomaof mucosal membranes, with a 7001000 fold increased incidenceof HNSCC [45]. Patients develop these tumors at a young age, evenin the absence of risk factors such as tobacco or alcohol exposure.The causative genes involved in these inherited syndromes func-tion in DNA repair and surveillance of genetic stability, which ex-plains a higher rate of cancer development in affected patients. Itremains unclear why affected patients feature a predilection forSCC development but it is of interest to note that sporadic HNSCCthat develop in the general population develop inactivation ofthese same genes (p53, p16, FANCA-M). These data suggest thatpathways involved in surveillance of genetic stability are keyevents in HNSCC development and predispose individuals to youngonset oral cancer when defects herein are inherited through thegermline. The identification and analysis of the HNSCC susceptibil-ity syndromes has contributed to early recognition of patients atrisk for young-onset HNSCC. Family histories may reveal importantclues for the presence of HNSCC susceptibility and genetic consul-tation is advised when a patient has multiple primary tumors, a tu-mor with rare histology, a tumor associated with congenitaldefects, inherited precursor lesions, or cutaneous lesions knownto be related to cancer susceptibility disorders (Table 2). A familyhistory of one first-degree relative with the same tumor and thesame clinical features, with two or more first-degree relatives withtumors at the same site or with two or more first-degree relativeswith rare tumors are also suspect for an underlying geneticdisorder [46].

In contrast to the dramatic phenotype of HNSCC inheritanceamong the small group of patients with inherited susceptibilitysyndromes, subtle forms of HNSCC susceptibility are a widespreadphenomenon among the general population. Retrospective studiesof large families have shown relative risks of around 3.6 for devel-oping HNSCC in individuals with a first degree relatives affectedwith HNSCC, suggesting that inherited factors contribute todevelopment of HNSCC [47,48]. Laboratory studies confirm theseobservations. For example, Bleomycin-based mutagen sensitivitycase-control studies have shown that patients with HNSCC havea significantly higher number of chromosomal breaks per Bleomy-cin-treated lymphocyte relative to healthy control populations[49]. Young patients with HNSCC appeared to be particularly sen-sitive to genotoxic stress showing a significantly higher number ofchromosomal breaks relative to matched older HNSCC controls.The same findings were reported in mutagen sensitivity studiesusing the classic tobacco carcinogen Benzo(a)pyrene diol epoxide(BPDE) instead of Bleomycin, and confirm that young patients withHNSCC are more vulnerable to the detrimental effects of tobaccoderived carcinogens relative to their non-HNSCC affected counter-parts. Studies of normal sequence variations present in the geno-mic blueprint of the general population (as represented by singlenucleotide polymorphisms; SNPs) have identified several SNPs that

Table 2Genetic cancer syndromes associated with HNSCC.

Syndrome Median age ofonset

Median agedevelopmentcarcinoma

Gene HNSCC Other cancers Clinical phenotype Testing

Fanconi anemia[58,59]

7 27 FANC family >500-foldhigher rate

Hematological Growth retardation (70% of cases) Chromosome breakage test in cells after culture withmitomicin C or diepoxybutane

Hyperpigmentation and/or caf au laitspots in 80%Skeletal malformations (60%), particularlyradial axis defectsProgressive bone marrow failureOther: renal anomalies, hypogonadism,mental impairment, heart defects,diabetes mellitus (10 to 30%

FAMMM [60] unknown 3345 CDKN2A Increased Melanoma, pancreas Families with melanoma (2 first-degreerelatives are diagnosed with melanoma, orfamilies with 3 melanoma patients,irrespective of degree of relationship)

Gene sequencing using blood/saliva or DNA

The co-existence of melanoma andatypical nevi within families

Targeted mutation analysis in blood

Early onset pancreatic carcinoma CDKN2A gene deletion/duplication tests in blood

Blooms syndrome(BSyn) [61]

Childhood 25 BLM (DNAhelicase)

Increased Multiple leukaemias,lymphomas and carcinomas

Dwarfism: intrauterine growthretardation

Cytogenetic and/or molecular analysis of BLM incultured blood lymphocytes

Hyperpigmented (cafe au lait) spots;hypopigmented areas; sun sensitivetelangiectatic erythema

Sister chromatid exchange (SCE) analysis in culturedcells of any type (standard)

Microcephaly; dolichocephaly; narrowface; prominent nose and/or ears;characteristic high-pitched voiceNormal intelligenceImmune deficiencyOther: myocardopathy; hypogonadism inmale patients; hypertriglyceridemia

Xerodermapigmentosum[62]

12 8 XP-A to XP-G

Increased UV-induced skin cancer Severe sun photosensitivity(poikilodermia); dry skin, senile-like,cutaneous retractions

Cellular hypersensitivity to UV radiation

Photophobia, followed by bilateralcataract; increased risk of ocular benignand malign tumors

Chromosomal breakage analysis in cultured cells

Neurological signs (14 to 40%); mentalretardation, pyramidal syndrome,peripheral neuropathy

Complementation test

Gene sequencing using blood/saliva or DNA

Ataxiatelangiectasia[63]

13 Early adult ATM Increased Leukemia, lymphoma Progressive cerebellar ataxia; oculomotorapraxia, dysarthria, and dystonia

Elevated level of alpha fetoprotein (AFP) in serum or inamniotic fluid

Telangiectasia Elevated level of carcinoembryonic antigen (CEA) inblood

Combined immunodeficiency (in 70 %):thymus hypoplasia, and IgG2 and 4, IgA,IgE deficiencyGrowth retardation; hypogonadism;occasionally diabetes mellitus

7;14 chromosome translocation on chromosomeanalysis of peripheral blood

LiFraumeni [64] Childhood-early adult

50% of patients before40

TP53 Increased Lymphoma, sarcoma No associated dysmorphologies orabnormalities

Sequence analysis for TP53 mutation using blood/salivaor DNA

FAMMM = Familial Atypical Multiple Mole Melanoma syndrome.ANCC = Fanconi Anemia, complementation group C.

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H.S. van Monsjou et al. / Oral Oncology 49 (2013) 10971102 1101may decrease the functionality of specific proteins and are associ-ated with increased risk of HNSCC development. Genes affected bysuch SNPs include genes involved in repair of tobacco induced DNAdamage, and prominent cell cycle regulators such as Cyclin D1(CCND1), p53 and P21 (Waf1/CIP1). Case control studies have iden-tified these SNPs at higher frequencies in the genomic blueprint ofHNSCC patients compared to that of healthy controls, with subtlerisk implications in the order of 28-fold for HNSCC development.Of special interest is a study of Storey and colleagues that demon-strates a specific polymorphism at codon 72 of the p53 gene thatmodifies susceptibility of p53 to HPV-mediated degradation andis associated with an accordingly increased risk of HNSCC develop-ment of about seven fold [5052]. Interestingly, patients whodeveloped HNSCC at a young age appeared to have the highestfrequency of risk-increasing SNPs [53]. Altogether, these datasuggest that genetic susceptibility factors may increase the riskof young-onset HNSCC, alone, or in combination with extrinsic riskfactors.Clinicopathological profile of young onset HNSCC

Several differences in clinicopathological profile between youngand older HNSCC patients have been observed. Young patients tendto have a higher proportion of early stage HNSCC. Plausibly, youngpatients are more alert on unusual and alarming signs in the oralcavity and may ask for professional consultation at an earlier stagethan older patients. HNSCC patients are often burdened with se-vere comorbidities due to life-long exposure to tobacco and alco-hol. In older patients, treatment modalities sometimes have to beadjusted because of these comorbidities. In contrast, young pa-tients typically lack significant comorbidity, and tolerate optimaltreatment better, which affects prognosis.

Accordingly, divergent outcomes of young onset HNSCC andadult HNSCC have been suggested but not unequivocally estab-lished. Since 1995, six studies have found a different disease spe-cific survival (DSS) for young onset HNSCC compared to olderHNSCC. Lacy and colleagues reported significantly superior sur-vival of HNSCC patients below the age of 40 years old, as comparedto patients 4164 years old and patients older than 65 years old[24]. However, these authors did not perform longitudinal survivalanalysis on their patients. Lee and colleagues reported superior(95% DSS) 5 year survival of 20 oral tongue cancer patients belowthe age of 45 years old, compared to 20 matched patients olderthan 45 years old (60% 5-year DSS) [54]. These differences re-mained significant after extending their analysis to include all oralcavity SCCs presenting to the department [54] and after the sur-vival estimates were computed with KaplanMeier disease-spe-cific survival curves. Funk et al. found a significant 5-yearrelative survival advantage (63.7%) for patients aged 35 years oryounger with oral cavity SCC compared to patients aged 3565and 66 years and older (51.0% and 47.6%). In contrast, Garavelloand colleagues found significantly decreased survival of oral ton-gue cancer patients below the age of 40 (5-year DSS: 34%), com-pared to their older counterparts (5 year DSS: 58%) [55]. Morrisand colleagues suggested that very young patients with oral cavitySCC (below the age of 20 years old), experience improved survivalcompared to adult patients, but these differences did not remainstatistically significant, after controlling for gender, stage, histo-logic grade and treatment modality in multivariate analysis [56].In contrast, several studies report no differences in clinical out-come between young onset and older HNSCC [27,57]. The retro-spective nature of previous studies likely contributes to theobserved variety in reported results. For example, multiple priorstudies have used matchedpair analysis, but this approach maybe limited due to a potential influence of non-matched variableson survival, and impossibility to perform multivariate analysis.Insufficient sample size in several prior studies has also precludedthe use of survival analysis and multivariable analysis. The trueimpact of young age on HNSCC clinical behavior will remaindifficult to determine unless multi-institutional databases will becombined.Conclusion

The unique epidemiologic, genetic, etiologic, and clinicopatho-logic characteristics of young-onset HNSCC suggests a divergentbiology from HNSCC occurring in older patients. Improved defini-tion of this biology is needed to establish successful preventiveand treatment deintensification efforts.Conflict of interest statement

None declared.References

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Head and neck squamous cell carcinoma in young patientsIntroductionIncidenceExtrinsic risk factors: tobacco and alcoholExtrinsic risk factors: HPVIntrinsic risk factorsClinicopathological profile of young onset HNSCCConclusionConflict of interest statementReferences