oral cancer-the importance of early diagnosis and treatment

Oral CancerThe Importance of Early Diagnosis and Treatment

James J. SciubbaDental and Oral Medicine Division, Otolaryngology, Head and Neck Surgery, Johns Hopkins Medical Center, Baltimore, Maryland, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2391. Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2402. Leukoplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

2.1 Proliferative Verrucous Leukoplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2422.2 Erythroplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

3. Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2423.1 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2423.2 Intra-Oral Carcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2433.3 Verrucous Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2453.4 Tumor Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2463.5 Histopathology of Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

4. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2475. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

Abstract Oral cancer is an important health issue. The WHO predicts a continuing worldwide increase in the numberof patients with oral cancer, extending this trend well into the next several decades. In the US the projectednumber of new cases of oral and oropharyngeal cancer will exceed 31 000 per year. Mortality due to cancers inthis region exceeds the annual death rate is the US caused by either cutaneous melanoma or cervical cancer.

Significant agents involved in the etiology of oral cancer in Western countries include sunlight exposure,smoking and alcohol consumption. Use of the areca or betel nut in many cultures is a major etiological factoroutside of the USA. Other etiologic factors associated with oral squamous cell carcinoma, but far less significantstatistically, include syphilis and sideropenic dysphagia. Recently, strong evidence for an etiological relation-ship between human papilloma virus and a subset of head and neck cancers has been noted.

It is generally accepted that most sporadic tumors are the result of a multi-step process of accumulated geneticalterations. These alterations affect epithelial cell behavior by way of loss of chromosomal heterozygosity whichin turn leads to a series of events progressing to the ultimate stage of invasive squamous cell carcinoma. Thecorresponding genetic alterations are reflected in clinical and microscopic pathology from hyperplasia throughinvasiveness.

A wide range of mucosal alternations fall within the rubric of leukoplakia. Proliferative verrucous leukoplakiarepresents a relatively new type of leukoplakia that is separate from the more common or less innocuous formof this condition. Erythroplakia is particularly relevant considering its almost certain relationship with dysplasiaor invasive carcinoma.

Squamous cell carcinoma will develop from antecedent dysplastic oral mucosal lesions if an early diagnosishas not been made and treatment given. Early diagnosis within stages I and II correspond to a vastly improved5-year survival rate when compared with more advanced stage III and IV lesions.

Surgical management of this disease remains the mainstay of treatment. Other therapies include radiationand chemotherapy options that may be used adjunctively and palliatively. Following treatment, it is importantto understand the significant risks of second primary cancers developing within the upper aerodigestive tract asa result of field cancerization. The most important message is that early detection of the asymptomatic earlystage oral cancer translates in general terms to satisfactory clinical outcome and cure in most patients.

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In the US the projected number of new cases of oral andoropharyngeal cancer will exceed 31 000 per year. Mortality dueto cancers in this region exceeds the annual death rate caused byeither cutaneous melanoma or cervical cancer.[1] Cancer rates inthe oral and oropharyngeal region represent approximately 3% ofall cancers in the US each year with such statistics being consis-tent over several decades.[2] Consistent with the stability of theratio of oral cancers to those of other regions is the essentiallysteady level of associated mortality which has not shown anylevel of improvement over the past 4 decades despite significantadvances in surgical resection techniques, reconstruction, radia-tion therapy and chemotherapy.[3] It is of note that more than 8400deaths related to oral cancer projected in 1999 were predicted,with nearly 50% of people with oral cancer projected to die within5 years as a direct result of this disease.[2] The incidence of oralcancer worldwide, however, continues to increase, despite annualoropharyngeal cancer statistics in the US stabilizing. The WorldHealth Organization predicts a continuing worldwide increase inthe absolute numbers of patients with oral cancer, extending thistrend well into the next several decades.[4] The dominant canceroccurring in the head and neck region is squamous cell carci-noma, when one excludes the major salivary glands as well as thenasal and paranasal sinus.[5] Taken as a whole, carcinomas repre-sent 98.1% of oral and head and neck cancers, with nearly 87%specifically designated as squamous cell carcinomas.

1. Etiology

Significant agents relative to the etiology of oral cancer inWestern countries include sunlight exposure (lower lip), smokingand alcohol consumption. Recent discussions have also included

the relative risks of smokeless tobacco as an additional etiologicalfactor within certain segments of the US population. The use ofthe areca nut or so-called betel nut in the form of a quid-contain-ing tobacco by many cultures is a major etiological factor outsideof the USA. Other etiologic factors associated with oral squamouscell carcinoma, but far less significant statistically, include syph-ilis and sideropenic dysphagia. The relationship between alcoholand tobacco use, however, remains the single most importantcause of oral cancer in that both of these agents act synergisticallyas far as carcinogenic potential is concerned. Strong evidence foran etiological relationship between human papilloma virus and asubset of head and neck cancers have been noted recently byGillison and her co-workers[6,7] with implications of sexual trans-mission being raised.

Specific causes aside, it is generally accepted that most spo-radic solid tumors are the result of a multistep process of accu-mulated genetic alterations.[8] A series of well defined clinicaland histopathological alterations for squamous cell carcinoma ofthe head and neck have built upon the model of Vogelstein andothers, which describes initiation, and progression of epithelialmalignancies including brain and bladder.[9-13]. A recent study byCalifano and colleagues[14] has proposed a genetic model forsquamous cell carcinoma development in the head and neck re-gion based upon allelic loss where the accumulation, and notnecessarily the order of genetic events, that determines progres-sion of disease. By analysing lesions of apparently benign mucosaadjacent to premalignant lesions, such early genetic events knownto exist in malignant cells may likewise be shared by those cells,which are morphologically benign. Subsequent genetic eventsand evolution of various subclones may produce phenotypic al-

Fig. 1. A nodular homogenous leukoplakia of the floor of the mouth.

Fig. 2. A diffuse, slightly lichenoid presentation of a leukoplakia in the retromolartrigone area.

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terations resulting in a variety of histopathologically altered re-gions in a local anatomic region. The subclone outgrowth willcontain acquired selective growth advantages and therefore pro-liferation abilities. It is through the sequential or progressive ge-netic alterations resulting in allelic loss which have helped definethe genetic progression model.

2. Leukoplakia

From the perspective of oral cancer development, under-standing the clinical and behavioral aspects of leukoplakia be-comes a necessity. The commonly accepted definition of oralleukoplakia is a clinical white patch on the oral mucous mem-branes that cannot be rubbed off or removed by scraping andcannot be classified clinically or microscopically as another dis-ease entity. By definition therefore, this represents a clinical di-agnosis only and can only be made by exclusion. This form ofmucosal alteration is the most common form of oral precancerand represents approximately 85% of oral premalignancy.[15-17]

It is important to note that the term leukoplakia is strictly a clinicalone without attendant biological or histopathological connota-tions and, therefore, no behavioral implication either. However,one may imply a potential for malignant or premalignant behaviorof such lesions until proven otherwise by adequate tissue sam-pling/biopsy. In the past, many pathologists as well as clinicians,including dermatologists, used the term leukoplakia synony-mously with a microscopic pathology, specifically epithelial dys-plasia or invasive carcinoma. Leukoplakia, therefore, can repre-sent a strictly benign hyperkeratotic lesion or may, in fact,represent a transformation from a benign lesion to that of a pre-invasive or invasive cancer characterized by various degrees of

dysplasia as intermediate morphologic steps. This, of course, willrule out other lesions which can likewise appear as oral whiteplaques, or alterations which include lichen planus, frictional ker-atosis or cheek biting, leukoedema, palatal nicotinic stomatitis,snuff dipper’s pouch keratosis and white sponge nevus.

A wide range of clinical presentation of leukoplakia exists(figs 1 to 4). This may range from a thin centrally translucentgrayish to gray-white surface with possible fissures or wrinkledsurface changes to areas which may be better defined, sharplydemarcated and firm. Such lesions may range from being focal,diffuse, smooth or homogeneous, to those which are heteroge-neous with granular or pumice-like surface qualities. More sig-nificant lesions may appear ulcerative, erosive, speckled or ver-rucous. Lesions with interspersed areas of erythroplasia oratrophic alterations within the white component (fig. 5) are com-monly associated with a higher risk of microscopic dysplasia andmalignant transformation.[18-22] A wide range of malignant trans-formation rates has been reported to be associated with leukopla-kias, ranging from 6.0 to 17.5% of cases.[18-20]

It must be emphasized that there are definitive behavioralqualities when leukoplakias are considered in aggregate relativeto anatomic site of presentation. Waldron and Shafer[23] empha-sized specific high risk locations, which include the floor of themouth, and ventral tongue regions, with a 40% demonstrated riskof dysplasia or carcinoma at the time of the initial biopsy fromthe floor of the mouth region. Also of note in this same large seriesof 3256 patients was the 3% frequency of carcinoma and 17% ofdysplasia.[23] Practical clinical experience has validated this par-ticular study and corresponds to the frequency of oral cancer de-

Fig. 3. A heterogeneous or speckled leukoplakia involves the ventral tonguesurface.

Fig. 4. A leukoplakia, proven to be dysplastic by biopsy, is thickened with focalerythroplakia noted along the palatal gingiva.

Oral Cancer: Early Diagnosis and Treatment 241


velopment at these sites in comparison to other locations withinthe oral cavity.

2.1 Proliferative Verrucous Leukoplakia

Other forms of leukoplakia in terms of clinical presentationhave been defined, in particular, proliferative verrucous leuko-plakia. Hansen and colleagues[24] have coined this term to de-scribe a form of leukoplakia, which tends to be persistent andinexorable in its march towards cancer development. The evolu-tion of this lesion from a clinical perspective begins as a simplehyperkeratosis, which is usually noted to present in multiplelocations simultaneously with gradual spread of individual fociresulting in fusion over time with similar adjacent foci. The pro-gress of the lesion is slow and may be measured over 1 to 2decades or more. The ultimate clinical pattern of the lesion maybecome tufted to verrucous and proliferative with a microscopicexpression ranging from papillary to a heavily keratinized onewith verrucous qualities and corresponding degrees of dysplasiaranging from mild to severe in nature.

The clinical and pathological correlation or prediction of thedysplastic or malignant potential of white lesions simply by clin-ical characteristics and location alone is not advisable and carriesa significant risk. In a large multicenter clinical trial, a panel ofexperienced clinicians evaluated oral leukoplakias where clini-cally benign appearing lesions were proven to be dysplastic orcarcinomatous through subsequent histological testing in 4.5% ofcases. Clearly, if such lesions had not been properly analyzed theywould have remained undiagnosed and conceivably allowed toprogress.[5] Implicit is an appropriate microscopic analysis of oral

mucosal white lesions at the time of clinical presentation usingscalpel biopsy techniques or a newly defined brush biopsy tech-nique, which utilizes a computer-assisted analysis of a repre-sentative sample of cells in disaggregated form.[25]

2.2 Erythroplakia

Prior to a more definitive discussion of oral squamous cellcarcinoma, one must include the clinical entity of erythroplakiaand its associated histopathology. The term erythroplakia embod-ies a clinical alteration of mucosa with no known associated eti-ology aside from those which we normally attribute to oral cancerdevelopment. It is best characterized as a well defined red patchor plaque with velvety surface qualities (fig. 6). Important in un-derstanding the relevance and significance of erythroplakia is thenear total association of this condition with either dysplasia orcarcinoma at the time of its initial clinical identification. Suchlesions tend to be predominantly located over the floor of themouth, soft palate and buccal mucosa. One may encounter theterm-speckled leukoplakia or erythroleukoplakia, which embodya blending or interspersal of white and red mucosal alterationsconcomitantly. This pattern likewise must be considered with ahigh degree of clinical suspicion, given the corresponding highrisk of microscopic dysplasia, if not invasive carcinoma.

3. Squamous Cell Carcinoma

Squamous cell carcinoma will develop from antecedent dys-plastic oral mucosal lesions if an early diagnosis has not beenmade and treatment rendered. From the standpoint of diagnosisat the clinical level any undiagnosed chronic ulceration of the oralmucosa or vermilion portion of the lips must always be consid-ered potentially malignant with a differential diagnosis to includean infectious or reactive processes as well as a neoplastic process.A definitive diagnosis must be based on a tissue biopsy.

3.1 Clinical Presentation

The lower lip vermilion is by far the most common site oforal cancer. This is usually attributable to years of exposure toultraviolet spectrum light with a lesser impact by pipe smoking.Carcinoma in this region of the oral cavity tends to be moreclosely related in behavior and presentation to cutaneous squa-mous cell carcinoma of the sun-exposed regions. The antecedentlesion is solar (actinic) cheilitis representing itself as a chronicprocess consisting of a mottled change of the surface of the lipwith a patternless mixture of erythema, pallor, and hyperkerato-sis. Erosion and ulceration are often superimposed upon thisbackground while effacement of the cutaneous-vermilion border

Fig. 5. Erythroleukoplakia or speckled leukoplakia involves the lateral aspect ofthe soft palate with extension to the retromolar trigone and inferiorly to the lateralpharyngeal wall.

242 Sciubba


is fairly common (fig. 7). Such changes develop over many yearsand very slowly, with a progression from a smooth to fissuredsurface to a crusted, rough, scaly and ultimately ulcerated surfacepresentation (fig. 8). Areas of exfoliation may be present with thepatient frequently reporting that the superficial crusts can easilybe removed, only to reform within 4 to 5 days.

As a precursor to squamous cell carcinoma, solar or actiniccheilitis is generally characterized at the histopathological levelby overlying atrophy of the surface stratified squamous epithe-lium alternating with thickened sheets of keratotic epitheliumwith well differentiated features including squamous pearl for-mation and variable levels of epithelial dysplasia (fig. 9). Char-acteristically, a lymphocytic infiltrate will be present within thelamina propria in intimate association with elastotic degenerationcharacterized as basophilic, amorphous and acellular areas repre-senting fragmentation of collagen and elastic tissue bundles andan abnormal ratio of the elastic to collagenous tissues. The squa-mous carcinoma arising within this context, in comparison to itsintra-oral counterpart, has a very good prognosis with an approx-imately 90% 5-year survival rate with metastases occurring inrelation to local but advanced disease. When metastasis does oc-cur, the regional submental (beneath the chin) lymph nodes areaffected first and are followed by the digastric, submandibularand more inferiorly based cervical lymph nodes.

3.2 Intra-Oral Carcinomas

Worldwide, intra-oral squamous cell carcinomas occurchiefly in men, often with a history of smoking and drinkingsignificant amounts of alcohol. However, in the US this genderbias has nearly equalized. A history of pre-existing mucosal al-

teration can usually be obtained from such patients with thosealterations ranging from 4 to 24 months in duration. During theearly phases of lesional growth the area involved is asymptom-atic, often leading to a degree of neglect on the patient’s part,which translates, to delay in establishing a professionally directeddiagnosis.

Most intra-oral squamous cell carcinomas will present in 1of 4 ways including a red patch, a white patch or an endophyticulcerative lesion and less commonly, a more exophytic mass withrolled margins, central ulceration and tissue friability. Frequently,the masses are nontender with any symptoms generally beingdisproportionate to the size of the lesion in question.

The dorsum of the tongue forms a tiny fraction of oral squa-mous cell carcinomas of the tongue in general. The posterolateraland ventral tongue surfaces account for nearly all tongue cancerswith the dorsum of the tongue being somewhat predisposed tocarcinoma development by the existence of longstanding atrophiclichen planus, lesions of tertiary syphilis, and lesions associatedwith chronic arsenic exposure. The non-oral or pharyngeal por-tion of the tongue, when involved with squamous cell carcinoma,is often associated with pharyngitis-type symptoms or with a de-gree of odynophagia or dysphagia. Occasionally, regional lymphnode metastases may be the only or initial indication of a primarybase of tongue squamous cell carcinoma.

At presentation the majority of tongue cancers are 2cm orgreater in dimension with one study indicating that 20% of 1289tongue cancers were in excess of 5cm.[26] In that study, directextension to the floor of the mouth, alveolar ridge, soft palate,pharyngeal wall or larynx was a typical finding in one-half of thepatients. Site of the tumor is certainly important in determining

Fig. 6. A well defined velvety red patch characterizes this erythroplakia in the softpalate area.

Fig. 7. The lower lip demonstrates effacement of the vermilion-cutaneous inter-face along with mottled, atrophic and superficial ulceration characteristic of earlysquamous all cell carcinoma.



the probable extent of such within the tongue with Easson andPalmer[27] finding that among 317 patients with squamous cellcarcinoma involving the anterior two-thirds of the tongue, more than60% were confined to the stage 1 category (fig. 10). Only 7.6%of those patients were placed in the stage 4 category. This iscontrasted to 149 patients presenting with posterior third tumorsalready showing 43% at the stage 4 level while only 22% were atthe stage 1 level of presentation.

Carcinoma of the floor of the mouth accounts for nearly one-third of all oral cancers with a recent increase in frequency notedin women. Pre-existing leukoplakia or erythroplakia is a commonprecursor of oral cancer at this site in particular. The anterior floorof the mouth in the vicinity of the lingual frenum and subman-dibular salivary ducts is the most common site within the floor ofmouth region to be affected by squamous cell carcinoma. Herethey often appear as an ulcerative lesion with irregular marginsand significant levels of induration (fig. 11). In advanced stagedisease, extension onto the gingiva and deep into the tongue mayoccur, with tongue fixation noted as a common finding. Moder-ately differentiated microscopic features are noted in most lesionsrelated to this particular anatomical site with metastatic lymphnode involvement usually found initially in the submandibulartriangle region and also the jugulo-digastric node and at the upperand middle levels (levels 1, 2, and 3) of the jugular chain.

Squamous cell carcinoma of the attached gingiva and alveo-lar gingival mucosa accounts for approximately 5% of intra-oralcarcinomas and usually presents as a painless lesion in the poste-rior mandibular segments. Bony invasion is often an early clinicalpresentation with well differentiated microscopic features identi-fied. Often it will be the case that the periodontal membrane will

be invaded directly by a gingival carcinoma, thus allowing easyaccess to the alveolar socket or alveolar segment of the jaw andsubsequent involvement of the medullary component of the man-dible (fig. 12). In this latter circumstance tooth mobility, as anisolated finding in the absence of periodontal disease elsewhere,may be one of the chief presenting findings. A further circumstancewhere gingival squamous cell carcinoma should be suspected isin the case of a nonhealing extraction site where the alveolarsocket may contain nodular masses of tissue, mimicking granu-lation tissue or a pyogenic granuloma.

The soft palate and adjacent retromolar trigone, inferiorly andlaterally, represents the site of approximately 15% of intra-oralsquamous cell carcinomas. In this area speckled leukoplakia/erythroleukoplakia or homogeneous erythroplakia, often withnodular features, are the usual presenting findings (fig. 13). In-duration in the central areas is characteristic while more periph-erally the lesions are usually less indurated and correspondingly

Fig. 8. A well developed lower lip squamous cell carcinoma with nodular, keratoticand exophytic growth features of nearly 2 years duration.

a

b

Fig. 9. Solar (actinic) cheilitis with dysplastic, noninvasive epithelial features, sur-face hyperkeratosis (a) and lymphocytic infiltrate within the papillary dermis (b).

244 Sciubba


less infiltrative. In contrast to more anteriorly placed squamouscell carcinomas, lesions in this location tend to be moderately topoorly differentiated, with deeper invasion associated with rela-tively small surface alteration. There is a corresponding increasedlevel of regional and distant spread at the time of initial diagnosiswhere patients will often state a complaint of pharyngitis-typesymptoms or odynophagia. When considering the hard and softpalate as a composite unit, 71% of squamous cell carcinomas arenoted to occur in the soft palate while 29% were found at theformer site.[28] Also of note is that nearly 40% of patients withsoft palatal primary tumors will develop regional lymph nodemetastases in contrast to only 13% of patients with similar sizedlesions involving the hard palate.

As a site, the buccal mucosa accounts for approximately 2%of oral squamous cell carcinoma. Cancer in this region is gener-ally asymptomatic. In its early phases most lesions tend to arisein the more posterior aspects of this area, usually presenting assmall ulcerated or indurated masses that are usually associatedwith a pre-existing leukoplakia and, much less commonly, aneythroplakia. Given the location of primary lesions at this site,they are often traumatized during routine daily function, oftenleading to ulceration. In more advanced stages, a degree of tris-mus may be present as well as alterations in the ability to masti-cate properly. Extension into the mucobuccal folds of the mandi-ble and maxilla is a finding in later stage disease, usually as acomponent of an exophytic growth phase. Occasionally, the car-cinoma may arise within the sulcus itself (usually in the mandib-ular sulcus). Left undiagnosed and untreated buccal mucosal car-cinoma can present as multiple cutaneous sinuses.

As noted above, a buccal mucosal carcinoma is not a com-monly noted form of intra-oral carcinoma in the US and Western

Europe. However, in other parts of the world, in particular Indiaand Southeast Asia, this is a much more common site of primarysquamous neoplasia. This is attributable to widespread use ofbetel quid and chewing tobacco. Lesions extending into the man-dibular mucobuccal sulcus from the buccal mucosa can grow intothe periosteum of the mandible allowing such to be fixed to thatlocation allowing subsequent invasion of the mandibular cortexand beyond.[29]

3.3 Verrucous Carcinoma

A distinct clinical pathological entity among oral carcinomasis the verrucous carcinoma first described in 1948 by Acker-man.[30] This lesion, while found at other sites, predominates inthe oral cavity. The most frequent site of such is the buccal mu-cosa while the alveolar ridge or gingiva accounts for nearly a thirdof cases and the floor of the mouth for approximately 10% ofsuch.

Clinically this tumor is initially soft and well defined. Overtime, however, it becomes more indurated, firm and more tufted.From the surface emanate numerous fronds or papillary projec-tions which are heavily keratinized and in some areas appear nod-ular, pebbled or fungating, usually without ulceration (fig. 14).Lesions of the buccal mucosa may extend into the buccal sulcusand adjacent alveolar ridge and have the ability to destroy boneslowly subsequent to becoming fixed to the overlying perios-teum, usually of the mandible.

This particular form of carcinoma does not typically metas-tasize locally or regionally as a result of its exceedingly blandhistological and behavioral patterns. From a clinical and histo-logical differential diagnosis standpoint, lesions to be considered

Fig. 10. A thin or superficial T1 cell carcinoma of the anterior third of the tongue.

Fig. 11. The floor of the mouth shows a large (5 to 6cm), ulcerated squamous cellcarcinoma with granular surface features.



include keratoacanthoma, verrucous hyperplasia, verruca vul-garis, and pseudoepitheliomatous hyperplasia. The overlying ep-ithelium is considerably thickened with an undulating papillatedsurface, which is densely keratinized over numerous fungatingfronds with inward or penetrating bulbous projections of reteridges. A well defined basement membrane is present along theinvasive growth front. The pushing, bosselated advancing mar-gins of this form of squamous carcinoma separate it from the moretypical and common infiltrative oral squamous carcinoma. Ofnote is a variably intense inflammatory infiltrate which is chieflylymphocytic in nature adjacent to the invading front of tumor.

3.4 Tumor Staging

Staging of oral squamous cell carcinoma will allow the cli-nician to determine prognosis based upon the components of thestaging criteria, which include tumor size, and the extent of met-astatic spread of the primary lesion. Staging involves a compositeof clinical parameter quantification with the components beingthe size of the primary tumor, (the T stage), the presence or ab-sence of regional lymph node involvement (N stage), and thepresence or absence of distant metastases (M stage). While thereare several published variations of the staging system, the TNMsystem is the most widely accepted one with high rates of corre-lation noted between stage level and 5-year survival rate. Table Idefines the criteria for the TNM system of staging while table IIdelineates the clinical staging categories and corresponding 5-year survival rates of oral (squamous cell) carcinoma. In additionto the universally accepted role of the TNM staging system rela-tive to overall rate of survival, additional factors including tumor

thickness, degree of tumor differentiation and vascular and peri-neural invasion likewise are important contributing factors.

3.5 Histopathology of Squamous Cell Carcinoma

Intra-oral squamous cell carcinoma may be viewed as an ex-tension of previously mentioned dysplastic or precancerous le-sions, which essentially represent the morphological expressionof the genetic alterations. The general morphology of the surfacestratified squamous epithelium in precancerous lesions tends tobe maintained in an overall sense. The majority of oral squamouscarcinomas are well differentiated or moderately differentiatedthus maintaining much of the structural resemblance to the tissueof origin. This also implies the presence of formed elements rep-resentative of the maturational process by way of keratin pearlformation and individual cell keratinisation or dyskeratosis.

The basement membrane zone represents the conceptual andquasi-physiological barrier, which separates an invasive from thepreinvasive or in situ lesion. Transgression beyond this marginby groups of cells or individual cells into surrounding and under-lying structures will confirm the nature of true invasive carci-noma (fig. 15a). Individual cells will demonstrate nuclei whichare hyperchromatic, enlarged, and with an increased level of mi-totic activity (fig. 15b). Nuclear alterations include pleomor-phism, coarse chromatin, thickened nuclear envelope, increasedvolume and often prominent nucleoli. In less well differentiatedlesions the proliferative cellular elements bear a lesser resem-blance to the tissue of origin (fig. 15c). Here the nuclei tend to belarger, somewhat more vesicular, while the cytoplasm shows lessevidence of keratinization with fewer cells demonstratinghyalinized to glassy eosinophilic cytoplasm, indicative of an

Fig. 12. A T1 squamous cell carcinoma originating along the junction of the alve-olar mucosa and attached gingiva.

Fig. 13. Central necrosis with a surrounding friable, erythematous collar of squa-mous cell carcinoma involving the soft palate.

246 Sciubba


early morphologic stage of keratin formation. Uncommonly,spindle cell patterns or sarcomatoid features may be seen (fig.15d). In such instances it is often the case where immunohisto-chemical techniques using antibodies to various molecularweight keratin species will be employed in order to unequivocallyidentify the cells as being of epithelial phenotype or origin.

The verrucous carcinoma can at times resemble a hyperplas-tic process rather than one, which is neoplastic in nature. Here themicroscopy is relatively bland and corresponds to the less aggres-sive clinical behavior pattern when compared to squamous cellcarcinoma in general. Such lesions demonstrate broad bosselatedpushing margins (fig. 16), which are unlike the finger-like infil-trative extensions into the underlying supportive tissue or bonecharacteristic of typical squamous cell carcinoma.

An aggressive variant of squamous cell carcinoma of surfaceorigin is the basaloid squamous cell carcinoma. This lesion tendsto arise in the oropharynx and base of tongue region with aggres-sive microscopic and corresponding clinical behavioral qualities(fig. 17). Misinterpretation of this lesion may occur with salivarygland adenocarcinoma and adenoid cystic carcinoma often beingconsidered in that context. Surface origin is usually demonstra-ble, however, when not present can often mislead a pathologist.

4. Treatment

Management of oral squamous cell carcinoma remains essen-tially surgically driven. The major determining factor regardingmanagement concerns itself with the clinical extent or stage ofthe disease at presentation, with treatment generally consisting ofa wide local to a more ‘radical’ removal. Radiation therapy or acombination of both radiation therapy and surgery, depending

upon clinical stage, are commonly employed dual managementmodalities.

While chemotherapeutic options remain available, it is usu-ally the case that such are employed in instances of large primarylesions, which are used adjunctively or palliatively in cases ofvery large or unresectable lesions. Such therapies, however, havenot been able to reduce mortality figures or extend prognosis,with, in fact, no significant level of overall survival noted overthe past 2 decades.[25] Intra-arterial chemotherapeutic techniquesmay be useful in cases of advanced primary lesions where palli-ation is desired, with further clinical trials underway in order todetermine efficacy.

Squamous cell carcinoma of the lower lip is generally con-sidered a purely surgical disease with wedge resection of un-equivocally invasive tumors. When larger lesions are present, orwhen clinically palpable lymph nodes in the submental and/or

Fig. 14. Thick, keratotic and exophytic in nature, this bulky verrucous carcinomainvolves the buccal mucosa with extension to the labial margin.

Table I. Tumor-node-metastasis (TNM) staging system for oral carcinoma

Primary tumor size (T)TX No available information on primary tumorTO No evidence of primary tumorT1S Only carcinoma in situ at primary siteT1 Tumor is less than 2cm in greatest diameterT2 Tumor is 2 to 4cm in greatest diameterT3 Tumor is more than 4cm in greatest diameterT4 Massive tumor greater than 4cm in diameter with

involvement of antrum, pterygoid muscles, base on tongue,or skin

Region lymph node involvement (N)NX Nodes could not be or were not assessedNO No clinical positive nodesN1 Single clinically positive homolateral node less than 3cm in

diameterN2 Single clinically positive homolateral node 3 to 6cm in

diameter or multiple clinically positive homolateral nodes,none more than 6cm in diameter

N2a Single clinically positive homolateral node 3 to 6cm indiameter

N2b Multiple clinically positive homolateral nodes, none morethan 6cm in diameter

N3 Massive homolateral node(s), bilateral nodes, orcontralateral node(s)

N3a Clinically positive homolateral node(s), one more than 6cmin diameter

N3b Bilateral clinically positive nodesN3c Contralateral clinically positive node(s)

Involvement by distant metastases (M)MX Distant metastasis was not assessedMO No evidence of distant metastasisM1 Distance metastasis is present



submandibular region are noted, a radical or a modified radicalcervical lymph node dissection is indicated.

Mandibular gingival primary tumors generally less than 3cmin greatest dimension can be treated by wide local excision includinga partial or marginal mandibulectomy or by radiation. For lesions

greater than 3cm, a more radical excision of the primary lesion isnecessary with inclusion of a lymph node dissection on the ipsi-lateral side. The role of postoperative radiation in the clinicallynegative neck may be performed prophylactically. If suspiciousor enlarged lymph nodes on the other hand are noted by imaging,or proven by tissue sampling, postoperative radiation therapy isindicated. Cady and Catlin[31] have indicated a 43% 5-year sur-vival rate for patients treated with surgery alone for squamouscell carcinoma involving the mandibular gingiva and approxi-mately 40% for similar lesions involving the maxillary gingiva.

For lesions of mandibular gingiva or floor of mouth origin,which invade the mandible, mandibular resection is required.These would include associated lymph node removal coupledwith postoperative radiation therapy. For small floor of mouth

Table II. Tumor-node-metastasis (TNM)a clinical staging categories for oralsquamous cell carcinomaStage TNM classification 5-year survival rate (%)I T1NOMO 85II T2NOMO 66III T3NOMO

T1, T2, or T3, N1MO41

IV Any T4 lesion, or any N2 or N3lesion, or any M1 lesion

9

a The TNM staging system for oral carcinoma is described in table I.

Fig. 15. (a) Early invasion by this well differentiated squamous cell carcinoma is noted with extension into the underlying lamina propria. (b) Mitotic activity ispresent within this moderately to poorly differentiated squamous cell carcinoma. (c) Nuclear pleomorphism, giant nuclei and total disruption of cellular differentiationcharacterizes this poorly differentiated squamous cell carcinoma. (d) Streaming, coherent sheets of spindle cells characterize the spindle cell variant of squamouscell carcinoma.

248 Sciubba


primary lesions less than 2cm in diameter (T1), wide local resec-tion or radiation therapy would be appropriate management.Treatment of deeply invasive lesions with elective radical neckdissections would be highly recommended, as would therapeuticlymph node dissection in the presence of palpable cervical lymphnodes or those, which are radiographically suspicious. The over-all control rate is approximately 66% with 65 to 85% survival forsmall lesions, while 50% survival at 5 years is noted for largerlesions treated by surgery and radiation. Patients treated with ra-diation alone for large lesions have a generally poor prognosis.[32]

The anterior two-thirds of the tongue, as the most commonsite of intra-oral cancer, carries a potential for early metastasis tosubmandibular and cervical lymph nodes. Small lesions (T1,stage 1) can be treated with a partial glossectomy or radiationtherapy with elective neck dissection being an option. Lesions 2to 4cm in greatest diameter (T2) require a wide removal resultingin subtotal resection with regional lymph node dissection, usuallyfollowed by radiation.[33]

The single most important variable relative to oral cancerpatients and their prognosis concerns the status of the drainingcervical lymph nodes. Cure rates decrease by approximately 50%when lymph metastasis is proven[34] or when contralateral lymphnodes are likewise involved. The metastatic potential will dependupon location of the primary lesion and clinical stage of the dis-ease in most circumstances. Other significant decreases in sur-vival have also been noted with regard to extracapsular spread oftumor[35] and involvement of multiple contralateral lymph nodes.The consensus being that elective lymph node dissection is indi-cated in high risk patients given the fact that those patients pre-

senting with metastases at follow-up were not candidates for sal-vage surgery approximately 50% of the time.[34]

Finally, the risk of second primary cancers developing withinthe upper aerodigestive tract following an oral cancer diagnosisremains a real one. The concept of field cancerization, which hasas its basis the numerous clonal genetic alterations within thesurface epithelial cell, induced by carcinogens and co-carcino-gens, supports such behavior.[36] The second primary cancer maybe defined as a malignancy developing at a geographically sepa-rate site from the primary lesion with intervening normal mucosa.The field cancerization concept, while not a new one, is supportedby newer developments in molecular biology, which include p53mutation and aneuploidy changes within the surface epithelium,among other genetic and molecular alterations. While oral cancerremains a significant, largely preventable disease, we remain witha generally poor 5-year survival pattern.

Early detection in the early asymptomatic stage greatly im-proves not only these rates but also patients’ quality of life as aconsequence of less radical and therefore debilitating treatments.As stated above, over 80% of patients with stage 4 disease willnot survive up to 5 years, while those with localized disease havean approximately 80% 5-year survival rate.[37] Further evidenceof the poor overall survival pattern is the 50% incidence of spreadto local/regional lymph nodes or metastases at the initial presen-tation.[38] Delay in performance of an appropriate biopsy as a keystep in recognizing early oral cancer contributes to greater mor-bidity, as does inappropriate therapy. One study has noted thatone-third of patients ultimately receiving an oral cancer diagnosiswere initially treated for other conditions.[39] For the clinician itis vital that apparently innocuous mucosal lesions receive early

Fig. 17. Central comedo-type necrosis is present within the basaloid squamouscell carcinoma.

Fig. 16. Verrucous carcinoma with rounded, ‘pushing’ advancing margins. A welldefined lymphocytic infiltrate and bland epithelial morphology further charac-terizes this lesion.



identification and microscopic characterization. Substantiatingthis is the estimate that, in the US adult population, only 25% ofleukoplakias are histologically evaluated.[15] Resulting from thisis the progression of unrecognized mucosal premalignancy to in-vasive cancer.

5. Conclusion

This article has discussed oral cancer from an etiologic, clin-ical, microscopic and behavioral prospective. The variable etiol-ogy of this important disease and the cultural variations in itspresentation make this a clinical challenge. Precursor lesions in-clude leukoplakia, in particular, proliferative verrucous leukopla-kia and speckled leukoplakia. The association between erythro-plakia and variable levels of dysplasia, if not squamous cellcarcinoma, must be appreciated at the time of diagnosis. Squa-mous cell carcinoma as well as verrucous carcinoma present tothe clinician specific anatomical preference sites and clinical ap-pearance. Tumor staging has been shown to be closely related toultimate behavior and prognosis of the lesion. Surgical manage-ment of this disease remains the mainstay of therapy. Other ther-apies include radiation and chemotherapy which may be usedadjunctively or palliatively. Following successful management oforal cancer one must remain vigilant regarding the increased in-cidence of second primary carcinomas of the upper aerodigestivetract as a result of field cancerization.

The most important message for clinicians is that early de-tection of the asymptomatic early stage oral cancer will translate,in general terms, to satisfactory clinical outcome and cure in mostinstances.

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Correspondence and offprints: Dr James J. Sciubba, Dental and Oral MedicineDivision, Otolaryngology, Head and Neck Surgery, Johns Hopkins MedicalCenter, 601 N. Caroline Street, 6th Floor, Baltimore, MD 212871, USA.E-mail: [email protected]



oral cancer-the importance of early diagnosis and treatment

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