bb9-chap4

CHAPTER 4

Tumours of the Oral Cavity andOropharynx

Squamous cell carcinomas amount to more than 90% of malig-nant tumours of the oral cavity and oropharynx. As in otherparts of the upper aerodigestive tract, there is a strong andsynergistic association with tobacco smoking and alcoholabuse. In some regions, particularly the Indian subcontinent,oral cancer is among the most frequent malignancies, largelydue to tobacco chewing. The WHO Working Group has made an attempt to unify the ter-minology used to define the histological features of precursorlesions throughout the head and neck region. Although therehas been considerable progress in the understanding of thegenetic and molecular events underlying the progression ofprecancerous lesions to invasive carcinomas, this has yet to betranslated into novel therapeutic strategies.

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164 Tumours of the oral cavity and oropharynx

WHO classification of tumours of the oral cavity and oropharynx

__________1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {821} and the Systematized Nomenclature of Medicine (http://snomed.org).

Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.

Malignant epithelial tumoursSquamous cell carcinoma 8070/3

Verrucous carcinoma 8051/3Basaloid squamous cell carcinoma 8083/3Papillary squamous cell carcinoma 8052/3Spindle cell carcinoma 8074/3Acantholytic squamous cell carcinoma 8075/3Adenosquamous carcinoma 8560/3Carcinoma cuniculatum 8051/3

Lymphoepithelial carcinoma 8082/3

Epithelial precursor lesions

Benign epithelial tumoursPapillomas 8050/0

Squamous cell papilloma and verruca vulgarisCondyloma acuminatumFocal epithelial hyperplasia

Granular cell tumour 9580/0 Keratoacanthoma 8071/1

Salivary gland tumoursSalivary gland carcinomas

Acinic cell carcinoma 8550/3Mucoepidermoid carcinoma 8430/3Adenoid cystic carcinoma 8200/3Polymorphous low-grade adenocarcinoma 8525/3 Basal cell adenocarcinoma 8147/3Epithelial-myoepithelial carcinoma 8562/3 Clear cell carcinoma, not otherwise specified 8310/3 Cystadenocarcinoma 8450/3 Mucinous adenocarcinoma 8480/3 Oncocytic carcinoma 8290/3 Salivary duct carcinoma 8500/3

Myoepithelial carcinoma 8982/3 Carcinoma ex pleomorphic adenoma 8941/3

Salivary gland adenomasPleomorphic adenoma 8940/0Myoepithelioma 8982/0Basal cell adenoma 8147/0Canalicular adenoma 8149/0Duct papilloma 8503/0Cystadenoma 8440/0

Soft tissue tumoursKaposi sarcoma 9140/3Lymphangioma 9170/0Ectomesenchymal chondromyxoid tumourFocal oral mucinosisCongenital granular cell epulis

Haematolymphoid tumoursDiffuse large B-cell lymphoma (DLBCL) 9680/3Mantle cell lymphoma 9673/3Follicular lymphoma 9690/3Extranodal marginal zone B-cell lymphoma of MALT type 9699/3Burkitt lymphoma 9687/3T-cell lymphoma (including anaplastic large cell lymphoma 9714/3Extramedullary plasmacytoma 9734/3Langerhans cell histiocytosis 9751/1Extramedullary myeloid sarcoma 9930/3Follicular dendritic cell sarcoma / tumour 9758/3

Mucosal malignant melanoma 8720/3

Secondary tumours

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165WHO and TNM classificaton

1 {947,2418}.2 A help desk for specific questions about the TNM classification is available at www.uicc.org/index.php?id=508 .

TNM classification of carcinomas of the lip and oral cavity 1,2

T – Primary tumour TX Primary tumour cannot be assessedT0 No evidence of primary tumourTis Carcinoma in situT1 Tumour 2 cm or less in greatest dimensionT2 Tumour more than 2 cm but not more than 4 cm in greatest dimensionT3 Tumour more than 4 cm in greatest dimensionT4a (lip)

Tumour invades through cortical bone, inferior alveolar nerve, floorof mouth, or skin (chin or nose)

T4a (oral cavity)Tumour invades through cortical bone, into deep/extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus, and styloglos-sus), maxillary sinus, or skin of face

T4b (lip and oral cavity)Tumour invades masticator space, pterygoid plates, or skull base;or encases internal carotid artery

Note: Superficial erosion alone of bone/tooth socket by gingival primary isnot sufficient to classify a tumour as T4.

N – Regional lymph nodes## NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single ipsilateral lymph node, 3 cm or less in great

est dimensionN2 Metastasis as specified in N2a, 2b, 2c belowN2a Metastasis in a single ipsilateral lymph node, more than 3 cm but

not more than 6 cm in greatest dimensionN2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm

in greatest dimensionN2c Metastasis in bilateral or contralateral lymph nodes, none more

than 6 cm in greatest dimensionN3 Metastasis in a lymph node more than 6 cm in greatest dimension

Note: Midline nodes are considered ipsilateral nodes.

M – Distant metastasis MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

Stage grouping Stage 0 Tis N0 M0Stage I T1 N0 M0Stage II T2 N0 M0Stage III T1, T2 N1 M0

T3 N0, N1 M0Stage IVA T1, T2, T3 N2 M0

T4a N0, N1, N2 M0Stage IVB Any T N3 M0

T4b Any N M0Stage IVC Any T Any N M1

## The regional lymph nodes are the cervical nodes.

TNM classification of carcinomas of the oropharynx 1,2

T – Primary tumour TX Primary tumour cannot be assessedT0 No evidence of primary tumourTis Carcinoma in situT1 Tumour 2 cm or less in greatest dimensionT2 Tumour more than 2 cm but not more than 4 cm in greatest dimensionT3 Tumour more than 4 cm in greatest dimensionT4a Tumour invades any of the following: larynx, deep/extrinsic muscle

of tongue (genioglossus, hyoglossus, palatoglossus, and styloglos-sus), medial pterygoid, hard palate, and mandible

T4b Tumour invades any of the following: lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, skull base; or encases the carotid artery

N – Regional lymph nodes## NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single ipsilateral lymph node, 3 cm or less in great

est dimensionN2 Metastasis as specified in N2a, 2b, 2c belowN2a Metastasis in a single ipsilateral lymph node, more than 3 cm but

not more than 6 cm in greatest dimensionN2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm

in greatest dimensionN2c Metastasis in bilateral or contralateral lymph nodes, none more

than 6 cm in greatest dimensionN3 Metastasis in a lymph node more than 6 cm in greatest dimension

Note: Midline nodes are considered ipsilateral nodes.

M – Distant metastasis MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

Stage grouping Stage 0 Tis N0 M0Stage I T1 N0 M0Stage II T2 N0 M0Stage III T1, T2 N1 M0

T3 N0, N1 M0Stage IVA T1,T2,T3 N2 M0

T4a N0, N1, N2 M0Stage IVB T4b Any N M0

Any T N3 M0Stage IVC Any T Any N M1

## The regional lymph nodes are the cervical nodes.

TNM classification of carcinomas of the oral cavity and oropharynx

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Tumours of the oral cavity and orophar-ynx may be either epithelial, mesenchy-mal, or haematolymphoid. The epithelialtumours may be classified as those orig-inating within the epithelium lining of theoral cavity and oropharynx and thosederived from salivary gland tissue. Bothwill be included in this chapter, includingprecursor lesions where appropriate.For the haematolymphoid diseases, thereader is referred to the WHO Classi fica -tion of Tumours of Haema topoietic andLymphoid Tissues {1197}, for mesenchy-mal ones to the WHO Classification ofTumours of Soft Tissue and Bone {775}.

Oral Cavity

The oral cavity extends from the lips to thepalatoglossal folds. The outer vestibule isenclosed by the cheeks and lips andforms a slit-like space separating it fromthe gingivae and teeth. It is limited aboveand below by mucosal reflections fromthe lips and cheeks.The space bordered by the teeth and gin-givae is the oral cavity proper. It is bound-ed inferiorly by the floor of the mouth andtongue and superiorly by the hard palate. The buccal mucosa extends from thecommissure of the lips anteriorly to thepalatoglossal fold posteriorly. It is lined bythick, non-keratinized stratified squamousepithelium and contains variable numbersof sebaceous glands (Fordyce spots orgranules) and minor salivary glands. Theduct of the parotid gland (Stensen’s duct)opens on a papilla or fold opposite theupper second permanent molar tooth.The mucous membrane related to theteeth is the gingiva. The gingival mucosasurrounds the necks of the teeth and thealveolar mucosa overlies the alveolarbone and extends to the vestibular reflec-tions. The junction between these twoparts is marked by a faint scalloped linecalled the mucogingival junction. The gin-gival mucosa is pink and firmly attachedto the underlying bone and necks of theteeth (attached gingiva) except for a freemarginal area. It is usually non-keratinizedor parakeratinized. The alveolar mucosais reddish and covered by thin, non-kera-

tinized stratified squamous epithelium.Minor salivary glands may be seen in thealveolar mucosa and occasionally theattached gingiva.The hard palate is continuous anteriorlywith the maxillary alveolar arches andposteriorly with the soft palate. A medianraphe extends anteriorly from this junctionto the incisive fossa into which thenasopalatine foramen opens. Most of thepalatal mucosa is firmly bound to theunderlying bone forming a mucoperios-teum. It is covered by orthokeratinizedstratified squamous epithelium and poste-riorly contains many minor mucous sali-vary glands.The oral part of the tongue (anterior twothirds) lies in front of the V-shaped sulcusterminalis. It is mobile and attached to thefloor of the mouth anteriorly by a medianlingual fraenum. The dorsal part is cov-ered by stratified squamous epitheliumand contains several types of papillae.The most numerous are the hair-like fili-form papillae which are heavily kera-tinized. There are less numerous andevenly scattered fungiform papillae whichform pink nodules and contain taste buds.Taste buds here and in other oral sites areoccasionally mistaken for junctionalmelanocytic proliferation or Pagetoid infil-tration. In front of the sulcus terminalisthere are 10-12 circumvallate papillae.These contain many taste buds on thesurface and in a deep groove that sur-rounds each papilla. In addition, the ductsof minor serous salivary glands

(von Ebner’s glands) open into the base ofthe groove. At the postero-lateral aspectof the tongue where it meets thepalatoglossal fold there are the leafshaped foliate papillae. These also maycontain taste buds on the surface and thecore of the papillae often contains lym-phoid aggregates similar to those in therest of the Waldeyer ring. In addition,there are minor salivary glands in theunderlying lingual musculature. The ven-trum of the tongue is covered by thin, non-keratinized stratified squamous epitheli-um which is continuous with similarmucosa in the floor of the mouth. Minorsalivary glands (glands of Blandin andNuhn) are present, predominantlytowards the midline and deep within thelingual musculature. They can extend toinvolve the tip of the tongue. The floor of the mouth is a horseshoe-shaped area between the ventrum of thetongue medially and the gingivae of thelower teeth anteriorly and laterally. Itextends to the palatoglossal folds distallyand is in continuity with the retromolar padbehind the lower third molar tooth. Themucosa covers the major sublingualglands and the submandibular(Wharton’s) ducts which open anteriorlyonto the submandibular papillae on eitherside of the median sublingual fraenum. Itis important to note that 75% of oral squa-mous cell carcinomas have been report-ed to arise in an area that comprises thefloor of the mouth and adjacent lingualmucosa, sublingual sulcus and retromolarregion {1767}. This region forms onlyabout 20% of the total mucosal area. Thezone of increased susceptibility has beencalled the ‘drainage area’ as it is thoughtthat any carcinogens present in the mouthpool there before being swallowed. It isobvious, therefore, that any precursorlesions in these areas should be regardedas highly suspicious.

Oropharynx

The oropharynx lies behind the oral cav-ity. It is bounded superiorly by the softpalate and inferiorly by a hypothetical

P.J. SlootwegJ.W. Eveson

Tumours of the oral cavity and

oropharynx: Introduction

Fig. 4.1 Taste buds. Normal intraepithelial tastebuds are sometimes confused with melanocyticlesions and pagetoid infiltration..

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167Introduction

horizontal line level with the tip of theepiglottis. Anteriorly are the isthmus ofthe fauces and the posterior third of thetongue, and the lateral wall is formed bythe palatopharyngeal arches and thepalatine tonsils. The posterior wall con-tains the pharyngeal tonsils. The palatine tonsils are two masses oflymphoid tissue situated in the triangularrecess (tonsillar sulcus) between theanterior and posterior faucial pillars.They extend from the soft palate to thedorsum of the tongue. The surface isconvoluted and deep clefts or crypts canpenetrate almost its full thickness. Thebulk of the tonsil consists of lymphoid tis-sue arranged in nodules or follicles.There are no afferent lymphatics and nosubcapsular sinuses. Squamous cellcarcinomas at this site can invadedeeply into the underlying tissues, baseof tongue and lateral pharyngeal wall.They also have a particular tendency toextend upwards into the nasopharynx.The soft palate is a mobile, muscular flapattached to the posterior edge of thehard palate and extending to a free mar-gin posteriorly. The uvula forms a small,conical, midline process. The oral sur-face of the soft palate is covered by non-keratinized stratified squamous epitheli-um and contains many minor mucousglands. The uvula contains mainly fatand a few muscle fibres but minor sali-vary glands may also be seen and occa-sionally salivary gland tumours developat this site.The pharyngeal part of the tongue isimmobile and has a bossellated surfacedue to the presence of underlying lym-phoid tissue forming the lingual tonsils.Minor salivary glands are also present.

Lymphatic drainage of mouth and

oropharynx

The main sites of lymphatic drainagefrom the mouth and oropharynx are thejugulodigastric, submandibular and sub-mental lymph nodes. Lymph vesselsfrom the gingiva usually drain to the sub-mandibular lymph nodes but those in thelower incisor region run to the submentalnodes. Most of the vessels from thepalate run to the jugulodigastric groupbut some involve the retropharyngealnodes. There is a rich lymphatic plexus inthe tongue and the main vessels can besubdivided into marginal and central.The marginal vessels drain the lateralthird of the dorsum and contiguous later-

al border and part of the ventrum of thetongue. They run to the ipsilateral sub-mandibular nodes. Those towards the tipof the tongue drain to the submentalnodes. Central lymph vessels drain to thesubmandibular nodes on both sides.Some marginal and central vessels rundirectly to the jugulodigastric group butsome can pass direct to the jugulo-omo-hyoid nodes. Vessels from the area of thecircumvallate papillae and posterior third

of the tongue drain to the jugulodigastric,jugulo-omohyoid or intermediate nodes,either unilaterally or bilaterally. Most ofthe lymphatics of the palatine tonsilsdrain to the jugulodigastric nodes.

Fig. 4.2 Global incidence rates of tumours of the oral cavity and oropharynx (all ages) in males. Age-stan-dardized rates (ASR, world standard population) per 100,000 population and year. From J. Ferlay et al.,Globocan 2000 {730}.

Fig. 4.3 Incidence and mortality rates for tumours of the oral cavity and pharynx (excl. nasopharynx), allages, in males. Age-standardized rates (ASR, world standard population) per 100,000 population and year.From J. Ferlay et al., Globocan 2000 {730}.

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Definition

An invasive epithelial neoplasm with vary-ing degrees of squamous differentiationand a propensity to early and extensivelymph node metastases, occurring pre-dominantly in alcohol and tobacco-usingadults in the 5th and 6th decades of life.

ICD-O code 8070/3

Epidemiology

More than 90% of malignant neoplasmsof the oral cavity and oropharynx aresquamous cell carcinomas of the liningmucosae with relatively rare neoplasmsarising in minor salivary glands and softtissues. It is important to specify whichanatomical sites are included in epidemi-ological data. Separate assessment ofincidence rates for the oral cavity andoropharynx is complicated by the diffi-culty of assigning a site of origin totumours that are often advanced.Males are affected more often thanfemales because of heavier indulgencein both tobacco and alcohol habits inmost countries: in India the highest ratesof intraoral cancer may be found inwomen who chew tobacco heavily. Themale to female ratio is, however, globallylower for cancer of the oral cavity than forcancer of the oropharynx, perhaps sug-gesting that higher exposure to tobaccosmoking and alcohol drinking arerequired to induce oropharyngeal thanoral cancer {796}.Globally some 389,650 cases occurredin the year 2000; 266,672 for the oralcavity (ICD-9 140-5) and 122,978 for theoropharynx (ICD-9 146,8-9) {1981}. Thisrepresents 5% of all cancers for men and2% for women. In males, the country with the highestrate in the western world is currentlyFrance, with extremely elevated ratesalso in French-speaking Switzerland,Northern Italy, Central and EasternEurope (especially Hungary) and parts ofLatin America. Rates are elevatedamongst both men and women through-out South Asia. In the USA incidencerates are two-fold higher in Black men

than White men {1981}. Very high rates inthe IARC database for Melanesia, pre-sumably associated with areca nut andtobacco habits, are based on small num-bers and need confirmation {730,1981}.The high incidence rates in Australasiaare explained by lip cancer in fair-skinned races which has a comparative-ly low mortality rate.Much of Europe and Japan is experienc-ing alarming rises in incidence, with astrong cohort effect, those born fromapproximately 1930 onwards showingsignificantly increased incidence andmortality. In North America there are sta-tistically significant falls in Whites, butBlacks continue to show worse out-comes. Globally, with the exception ofthe most highly specialized treatmentcentres, survival rates have not improvedfor decades.Significant increases in incidence inyounger subjects, particularly males,have been reported from many westerncountries in recent decades {1534,2259}.

Etiology

Tobacco smoking and alcoholThe dominant risk factors are tobacco useand alcohol abuse, which are stronglysynergistic {228}. Alcohol and tobaccoaccount for 75% of the disease burden oforal and oropharyngeal malignancies inEurope, the Americas and Japan{227,1862}. For the highest levels of con-sumption compared to the lowest onesrelative risks from 70 to over 100 havebeen shown {287,1811}. Relative risks incase-control studies showing a supermul-tiplicative effect in the oral cavity, betweenadditive and multiplicative in the oesoph-agus, and multiplicative in the larynx,reflecting degree of contact with boththese agents at these sites {797}.Most of the rise in western countries inrecent years has been attributed to risingalcohol consumption in northern Europe{1597 and rises in tobacco consumptionin parts of southern Europe. Significantrisk increases have also been reportedamongst non-drinking smokers and, to alesser extent, non-smoking heavy

Squamous cell carcinoma N. JohnsonS. FranceschiJ. FerlayK. Ramadas

S. SchmidD.G. MacDonald

J.E. BouquotP.J. Slootweg

Fig. 4.4 Trends in mortality from cancer of the oral cavity and pharynx in some European countries. Thelarge differences observed (currrently 10-fold in between Hungary and Finland) largely reflect past successand failure in tobacco and alcohol control. From F. Levi et al. {1483}.

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169Squamous cell carcinoma

drinkers {1406}. Studies that haveattempted to estimate a differencebetween wine, beer and hard liquors gen-erally indicate that heavy consumption ofall types of alcoholic beverage confersrisk, the differences in risk estimatesbeing largely due to socio-cultural corre-lates of drinking patterns in various popu-lations {142,1404}.Ultraviolet light and contact with smokingappliances are important for lip vermil-lion.

Tobacco chewingOral smokeless tobacco is a major causeof oral {969} and oropharyngeal {2908}squamous cell carcinoma in the Indiansubcontinent, parts of South-East Asia,China and Taiwan and in emigrant com-munities therefrom, especially when con-sumed in betel quids containing arecanut and calcium hydroxide (lime). Arecanut has been declared a known humancarcinogen by an IARC Expert Group(2003). In India chewing accounts fornearly 50% of cancers of the oral cavityand oropharynx in men and over 90% inwomen {108}. Traditional tobacco prod-ucts used in Sudan and the Middle East,which are powdered and fermented andmixed with sodium bicarbonate, containvery high levels of tobacco-specificnitrosamines and are highly carcinogenic{1171}. Those forms of non-flue curedsmokeless tobacco used as oral snuff inScandinavia and North America is lesscarcinogenic {1230} – though they causenicotine addiction.

Human papillomavirus (HPV) infectionHPVs, especially those genotypes ofknown high oncogenic potential in uterinecervix and skin such as HPV 16 and 18,are found in a variable but small propor-tion of oral, and up to 50% of tonsillar andoropharyngeal SCCs, especially the ton-sil. Recent studies suggest that HPV maybe responsible for a small fraction of oral,and up to 40% of oropharyngeal, cancers{888,1077}. This has lead to speculationthat HPV infection, perhaps arising fromoral/genital contact, might be important insome cases {2284}. Of interest is theobservation that HPV-containing cancersat these sites do not generally show TP53mutations, contrary to HPV DNA-negativecancers {660,1077}. It is well known thatHPV 16 E6 protein inactivates p53 pro-tein, suggesting that HPV and smokingmight operate, in part, on the same criti-

cal step in the multistage process of car-cinogenesis at these sites.

PreventionRecent work on risk factors in youngercases emphasises the importance ofearly and heavy tobacco and alcoholuse, the protective effect of diets rich infresh fruits and vegetables, but with asubstantial minority without these estab-lished risk factors {1534}.The protective effect of diets rich in traceelements and antioxidant vitamins is welldemonstrated in many countries, espe-cially in Italian studies {1628,2563}.Though more controversial, a contributionfrom poor oral hygiene is also suggested{108,2548}.

Second primary tumours

It has been recognised for a long time thatpatients with oral cancer are at risk of second tumours in the upper aerodiges-tive tract. This has been reported to occurin 10-35% of cases {2676}. These may besynchronous with the index tumour or, ifoccurring after an interval of longer thansix months are described as metachro-nous. Recurrence of the index tumourafter treatment can be diagnosed by thepathologist where the tumour is in deepertissue and not associated with the epithe-lial surface. However, the most frequentsituation of second tumours is when they

arise from surface epithelium adjacent tothe treated index tumour. On morphologi-cal grounds these are diagnosed as sec-ond primary tumours. The increasing useof molecular biological techniques hasallowed distinction to be made betweenmolecularly distinct second primarytumours and second field tumoursderived from the same genetically alteredfield as the index tumour {248}.

Localization

Tumours may arise in any part of the oralcavity. The most common sites vary geo-graphically reflecting different risk fac tors.Lip SCC arise almost exclusively on the lower lip. Within the oral cavity, thesubsites at which tumours may be locatedinclude: buccal mucosa, upper and lower gingiva, hard palate, anterior two-thirds of the tongue, including dorsal, ventral and lateral surfaces, and the floorof mouth. Many tumours are large at pres-entation and the tumour site is thenrecorded as essentially the centre of thetumour. Analysis of small symptomlesstumours shows the highest frequency infloor of mouth, ventrolateral tongue andsoft palate complex {1655}. This sug geststhat tumours arise at these sites, butspread preferentially to involve other sitessuch as tongue, being then recorded as lingual lesions. The clinical relevanceof this observation is to emphasise the

DC

BA

Fig. 4.5 Squamous cell carcinoma. A Exophytic growth involving the left buccal mucosa and overlying skinin a 65 year old male who chewed betel quid and smoked tobacco. B An exophytic growth arising from theleft palate. C Squamous cell carcinoma of the tongue. D Early squamous cell carcinoma of lateral borderof the tongue.

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importance of close examination of high-risk sites. The oropharynx consists of thebase of the tongue (posterior third), val-lecula, tonsil with tonsillar fossae and pil-lars, glossotonsillar sulci, posterior walland superior wall composed of the inferi-or surface of the soft palate and the uvula.The most common oropharyngeal site ofinvolvement for SCC is the base oftongue.

Clinical features

Signs and symptomsPatients with small oral and oropharyn-geal SCC are often asymptomatic or maypresent with vague symptoms and mini-mal physical findings. Hence, a highindex of clinical suspicion is needed todiagnose small lesions, especially if thepatients have tobacco and alcoholhabits. Patients may present with red

lesions, mixed red and white lesions, orwhite plaques. Co-existing white plaques(leukoplakia) may be observed adjacentto carcinomas and this implies an originin a pre-existing white lesion though theprevalence of this association variesconsiderably in different populations. However, most patients present withsigns and symptoms of locally advanceddisease. The clinical features may varyaccording to the affected intraoral sub-site. Mucosal growth and ulceration,pain, referred pain to the ear, malodourfrom the mouth, difficulty with speaking,opening the mouth, chewing, difficultyand pain with swallowing, bleeding,weight loss, and neck swelling are thecommon presenting symptoms of locallyadvanced oral and oropharyngeal can-cers. Occasionally, patients present withenlarged neck nodes without any symp-

toms from oral or oropharyngeal lesions.Extremely advanced cancers present asulceroproliferative growths with areas ofnecrosis and extension to surroundingstructures, such as bone, muscle andskin. In the terminal stages, patients maypresent with orocutaneous fistula,intractable bleeding, severe anaemiaand cachexia.Cancer of the buccal mucosa may pres-ent as an ulcer with indurated raisedmargin, exophytic or verrucous growth orwith the site of origin depending upon thepreferential side of chewing and place-ment of betel quid. In advanced stages,these lesions infiltrate into the adjacentbone and overlying skin. Cancer of thetongue may appear as a red area inter-spersed with nodules or as an ulcer infil-trating deeply, leading to reduced mobil-ity of the tongue. These tumours are

Fig. 4.6 A Well-differentiated squamous cell carcinoma (SCC), characterized by abundant formation of keratin pearls. B Moderately differentiated SCC. Cells formlarge anastomosing areas in which keratin pearls are formed. They are not very numerous and the main component consists of cells with pronounced cytonuclearatypia.

BA

Fig. 4.7 Poorly differentiated SCC. A Cells with atypical nuclei and a small rim of eosinophilic cytoplasm form strands and small nests. B Cells in a poorly differen-tiated SCC tend to have more vesicular nuclei. The cells in this tumour are more cohesive, forming larger tumour areas than the lesion shown in A.

BA

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painful. Cancers of the floor of mouthmay arise as a red area, a small ulcer oras a papillary lesion. Most patients pres-ent with discomfort or irritation at the siteof the tumour. Advanced stages areassociated with drooling. Cancers of thelower lip usually arise in the vermilionborder and appear as a crusty induratedor ulcerated lesion. Cancers of the upperlip are rare, often originate on the skinand spread to the mucosa. Cancer of thegingiva usually presents as an ulceropro-liferative growth. Tumours of the alveolarridge may occasionally present as diffi-culty in wearing denture plates or asloosening of teeth associated with painand bleeding during brushing of teeth.Tumours of the hard palate often presentas papillary or exophytic growths, ratherthan a flat or ulcerated lesion. Cancer of soft palate and uvula often

appear as an ulcerative lesion withraised margins or as fungating masses.Tonsillar cancers generally appear as anexophytic or ulcerative lesion.Sometimes they can present as enlargedneck nodes without any other signs andsymptoms. Cancer of the base of tonguepresents late in the course of the diseaseas a grossly ulcerated, painful, induratedgrowth. More than two-thirds of the patients withbuccal mucosal and gingival cancers inSouth Asia present with submandibularlymph node enlargement. More thanthree fourths of patients with tongue, floorof mouth and oropharyngeal cancers inSouth Asia present with neck swellingsimplying clinically obvious lymph nodemetastasis. In the West lymph nodeinvolvement is common at presentationin oropharyngeal SCC.

ImagingIntraoral and dental radiographs, in com-bination with orthopantomography, mayhelp in identifying involvement of theunderlying bone. Three-dimensionalimaging with computed tomography (CT)and magnetic resonance imaging (MRI)is frequently used to supplement the clin-ical evaluation and staging of the primarytumour and regional lymph nodes. CTscan or MRI give more information aboutthe local extent of the disease and alsohelp to identify lymph node metastases.CT scanning is useful in evaluatinginvolvement of cortical bone. MRI is moreinformative when evaluating the extent ofsoft tissue and neurovascular bundleinvolvement. The combination of soft tis-sue characterisation and anatomicallocalization afforded by CT and MRI make them valuable tools in the

Fig. 4.8 Squamous cell carcinoma (SCC). A Growth pattern of a diffusely infiltrating SCC. In this moderately differentiated lesion, the tumour cells form tiny strands.This growth pattern is a prognostically unfavourable feature. B Moderately differentiated SCC growing in large cohesive fields. This pattern is prognostically morefavourable than the diffuse growth shown in Figure A.

BA

Fig. 4.9 Squamous cell carcinoma (SCC). A In this moderately differentiated SCC, the tumour stroma contains a dense lymphoplasmacytic infiltrate. B SCC withperineural growth, spreading alongside the inferior alveolar nerve.

BA

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preoperative assessment of patients withoral or oropharyngeal cancers. Distantmetastasis from oral and oropharyngealcancer is uncommon at presentation. Atminimum, a routine radiograph of thechest is performed to rule out lungmetastases.

Relevant diagnostic proceduresOptimal therapy and survival from oralcancer depend on adequate diagnosisand assessment of the primary tumourand its clinical extent. Physical examina-tion should include visual inspection andpalpation of all mucosal surfaces, biman-ual palpation of the floor of the mouth,and clinical assessment of the neck forlymph node involvement. The diagnosis is confirmed by biopsy.The specimen is taken from the clinicallymost suspicious area, avoiding necroticor grossly ulcerated areas, and more thanone biopsy site may need to be chosen.In patients with enlarged cervical lymphnodes and an obvious primary in the oralcavity or oropharynx, the biopsy is alwaystaken from the primary site and not fromthe lymph node. In such situations, fineneedle aspiration cytology may be car-ried out to verify the involvement of thenode. If no obvious primary site is found inpatients presenting with neck nodes, fine-needle aspiration of the lymph node canbe performed to help establish the diag-

nosis. In patients for whom fine needleaspiration is non-diagnostic and SCC isstrongly suspected, excisional lymphnode biopsy is a last resort, as subse-quent curative therapy may be compro-mised by this procedure. The search foran occult primary tumour may includedirect pharyngolaryngoscopy with biopsyof high-risk sites like base of tongue,nasopharynx, and usually a diagnostictonsillectomy, as well as other imagingmodalities. Open lymph node biopsy iscarried out only when the lesion cannotbe identified by aspiration biopsy or inpatients with suspected lymphoma.Patients with SCC of the oral cavity ororopharynx have a risk of multiple pri-mary tumours in the pharynx or larynx, aswell as in the tracheobronchial region andoesophagus so routine panendoscopy isoften performed to evaluate these sites.

Tumour spread and staging

Staging is carried out according to theTNM classification {947,2418}. Recentadditions to the coding have been pro-vided for micrometatses, isolated tumourcells, findings in sentinel nodes andtumour detection by molecular methods.Some of these are discussed in the fol-lowing sections.Local spread of oral SCC, in the early

stages, is relatively predictable in tissuesthat have not been previously irradiated.It is influenced by local anatomical fea-tures. Lip SCC spreads superficially andthen into deeper tissues. Floor of mouthSCC spreads superficially rather than indepth, being unlikely to invade into themylohyoid muscle or the sublingualgland until a late stage. Tumour involvingthe lateral margin of tongue, whetherarising there directly or by superficialspread from the floor of mouth, tends tospread in depth. The intrinsic muscles oftongue run in small bundles in all direc-tions such that invading tumour encoun-ters some muscle running at right anglesto the surface. The line of least resist-ance to tumour spread is therefore alongthese muscle bundles and into thetongue. Tumours of palate spread super-ficially rather than in depth and this isalso true for more posterior tumours ofthe oropharynx. For most oral SCC other than tongue, theextent of spread in an area can be pre-dicted from the extent of surface involve-ment. Tongue and tonsil tumours canspread beneath intact normal appearingsurface, giving a larger area of tumourinvolvement. Spread of oral SCC intobone is a frequent problem. The mandibleis involved much more frequently than the

DCFig. 4.11 Squamous cell carcinoma (SCC). A Superficial erosion of the mandibular bone has perforated thecortical bone. As there is no spread in the bone marrow, this case of SCC does not meet the requirementsfor classification as T4. B Saucerization by SCC. In this case of, there is substantial loss of bone due toendocortical tumour growth (meets the requirements T4). C Permeative infiltration of bone by SCC growingdiffusely in the marrow cavities of the mandibular bone (T4). There is also heavy osteoclast-mediated boneresorption. D Bone invasion by SCC with diffuse growth in the mandibular bone.

BA

Fig. 4.10 Periodontal ligament involvement by asquamous cell carcinoma (SCC).

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maxilla. In dentate jaws the usual route ofentry into mandible is along the periodon-tal ligament. In edentulous areas ofmandible the tumour spread is throughthe crest of the alveolus directly into themarrow spaces between trabeculae ofcancellous bone {1682}. This occursbecause of failure of formation of an intactcortex of alveolar bone as resorption ofedentulous alveolus progresses. Tumoursin the mandible can involve the inferioralveolar nerve {1683} with a particularlikelihood of spread posteriorly along thenerve, sometimes extending well beyondthe mandibular foramen. Cancers arisingin gingiva or alveolus and those involvingthese sites by extension from adjacentsites are unlikely to invade into themandible other than by periodontal liga-ment or the crest of edentulous alveolus.Extension into the mandible throughforamina, for example the mental foramenfrom lip cancer, does occur, but is uncom-mon.

Spread in previously irradiated tissuesTumour spread in previously irradiatedsoft tissues tends to be more extensiveand less predictable than in normal tis-sues and as a consequence requiresmore extensive surgery if excision isattempted. Tumour invasion into irradiatedmandible tends to occur wherever thetumour approaches bone, often at multi-ple sites {1682}.

Lymphatic spreadSpread to local lymph nodes worsens theprognosis in oral and oropharyngeal can-cer. The mechanism of spread from theprimary site to lymph nodes is almostalways by embolism. Permeation in lym-phatics adjacent to tumours is uncommonand it is debatable if this spread extendsas far as lymph nodes. Once tumour ispresent in the neck, however, spreadbetween nodes may be embolic or bypermeation. The lymph nodes in the neckare divided into levels. The lymphatic dra-ianage from different head and neck sitesis realtively predictable {1789}. Levels athigh risk for metastasis from oral cavitySCC are Levels I, II and III, and to a less-er extent Level IV. Although Level II is themost frequently involved, some tumoursspread to Level III or IV, with or withoutinvolvement of Level I. This has given riseto the concept of skip metastsasis. In real-ity the lymphatic drainage is complex anddoes not follow a regular sequence of lev-

els of involvement in many patients{2817}. Bilateral spread to the neck is like-ly to occur from tumours involving themidline, especially tumours of posteriortongue or soft palate. Extracapsularspread of tumour involving lymph nodesis associated with a poor prognosis{2819}.There have been many studies attemptingto predict the presence of lymphaticspread from features of the primarytumour {872,2820}. Tumour size and siteare relevant. Tumour differentiation is nota reliable predictor. The pattern of theinvasive front is a useful predictor in that anon-cohesive front is associated withincreased likelihood of metastasis. Otherfactors associated with increased risk ofmetastasis are perineural spread at theinvasive front, lymphovascualr invasionand tumour thickness. The tumour thick-ness is measured from the deepesttumour invasion to the presumed originalsurface level, that is, ignoring exophyticgrowth or assessing the original surfacelevel in ulcerated tumours. For diagnosticpurposes a thickness of 5mm or greater isused as indicating increased risk of nodalspread {395}.

Haematogenous spreadUntil relatively recently, haematogenousspread of oral and oropharyngeal cancerhas been regarded as less important thanlocal and lymphatic spread. However, itsimportance is increasing as loco-regionalcontrol improves. Blood borne spreadmost often involves lung {754,1958}. Thebest predictor of the likelihood of thisspread is involvement of the neck at mul-tiple levels. This suggests that the route ofentry of tumours into the circulation ismost often via the large veins in the neckand that haematogenous spread is ineffect tertiary spread following extracap-sular spread from neck nodes.

Sentinel node biopsy

This is currently an experimental tech-nique {2057} that is under active evalua-tion by prospective clinical trials and it isnot practised at all centres. It is a tech-nique used primarily for staging a clinical-ly N0 neck. in an effort to avoid a neckdissection. If a clinically N0 neck is fol-lowed untreated until tumour develop-ment occurs, the prognosis can be verypoor {57,977}. Studies on the incidence ofoccult metastases in N0 necks {753} haveshown tumour spread in only a small

minority of patients. Therefore, if neck dis-section is undertaken either prophylacti-cally or as a staging procedure, onpatients with N0 necks, a large majoritywill have unnecessary surgery, as theneck will be found to be free from tumour. The sentinel node is the first draininglymph node from a tumour. It is assumedthat if the sentinel node can be shown tobe free from tumour, then the lymphaticbasin is free from tumour and neck dis-section is not required. By contrast, sen-tinel node positive patients can be select-ed for further therapy. Sentinel nodes areidentified by a combination of lym-phoscintigraphy and injection of blue dyein the tumour bed and then samplingdraining nodes identified. In reality, morethan one sentinel node is found in manycases {2345} indicating that tumoursdrain to more than a single first echelonnode, presumably from different parts ofthe tumour. Sampled sentinel nodes should be fullyexamined by the pathologist. This usuallyinvolves bisecting the node in the largestdiameter and then undertaking extensivesampling. Some pathologists undertakefrozen sections on bisected fresh nodes.If this is done it is important to use a tech-nique whereby the cut surface is frozenon a flat surface and only early sectionsare examined. This is to ensure that as lit-tle node as possible is examined at thisstage in order not to compromise fullexamination of the node. Paraffinprocessed blocks are then examined withH and E sections of the early sections ofthe blocks. If these show no tumour, moredetailed sampling with immunocytochem-istry for cytokeratins and samplingthrough the block is required. True serialsectioning is impracticable for routineuse. A compromise is step sectioning atintervals of 150µm with examination of Hand E sections and AE1/3 reacted sec-tions {2202}. The importance of thesesections is that suspicious areas onimmunocytochemistry can be identified inthe H and E sections. These may beviable tumour cells, but other possiblecauses of cytokeratin positivity, such asinclusion of normal salivary gland epithe-lium or thyroid follicles, either occultmetastases or lateral aberrant thyroid,need to be identified. Another not infre-quent finding is areas of cytokeratin posi-tivity which on H and E appear as dense-ly eosinophilic apparently non-viabletumour cells.

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Interpretation of sentinel nodes candemand considerable pathologicalexpertise. The outcome of the pathologi-cal assessment may be the presence ofmetastasis; micrometastasis, less than2mm diameter tumour deposits, or isolat-ed tumour cells {2477}. Micrometastasishas been defined {1073} as cells whichhave arrested and implanted. These maybe in contact with a vessel or lymph sinuswall or may be extravascular. Single orsmall clusters of cells within lymph orblood vessels, but not in contact with thewall are defined as isolated tumour cells.

Histopathology

The histological features of SCC havebeen discussed in Chapter 3 on tumoursof the hypopharynx, larynx and trachea.The findings in the oral cavity andoropharynx do not differ significantly fromthose of the larynx and hypopharynx. Aminority of oral and oropharyngeal can-cers show different histological subtypesthat can be associated with differences inprognosis. These are discussed below. Itis clearly important that pseudo epithe-liomatous hyperplasia (PEH) is distin-guished from SCC. PEH can occur inmucosa overlying a granular cell tumour,in necrotising sialometaplasia and in pap-illary hyperplasia of palate. PEH occurringwith mucositis, particulary after irradia-tion, may be difficult to distinguish fromsquamous cell carcinoma. The majority of cases of SCC present nodifficulty in diagnosis for the experiencedpathologist. However, the recognition ofthe earliest stages of invasion can beproblematic. No consistent guidelines forthis exist. The deepest layers of theepithelium and the interface between theepithelium and the lamina propria need tobe examined in detail. This is frequentlymade more difficult where there is aprominent inflammatory infiltration.

Relevant features include the loss of a his-tologically well-defined interface,described previously as loss of basementmembrane and disturbed architecture ofthe basal layers of the epithelium, particu-larly the replacement of basal cells bylarger irregular cells with cytoplasmicprocesses extending into connective tis-sue. In some cases the degree of cyto-logical atypia and mitotic feature maysuggest malignancy, but these are notalways present. To an extent the judge-ment about early invasion is subjectiveand it can be important for the pathologistto communicate the difficulty in interpreta-tion to the clinician. Some pathologists willindicate that while no unequivocal evi-dence of invasion is demonstrated, theynevertheless feel that the lesion should beregarded as early invasive carcioma.

Somatic genetics

There is some variation in the genetic pro-file of oral and oropharyngeal SCC thatreflects the site-specific impact of variouscasual agents and differences in clinicalpresentation. The carcinogens in tobaccosmoke, for example, increase the preva-lence and spectrum of TP53 mutations{268}. Compared to carcinomas that arisein patients who smoke, carcinomas inpatients who have never smoked harbourfewer p53 mutations, disproportionatelyinvolve women, typically arise from theoral tongue, and affect very young or veryold patients {1351,2258}. For carcinomasof the oropharynx, oncogenic humanpapillomavirus (HPV), particularly theHPV-16 subtype, is an importantcausative agent: More than 50% oforopharyngeal carcinomas harbour inte-grated HPV DNA {60,888,1999}. The E6and E7 viral oncoproteins bind and inac -tivate the TP53 and retinoblastoma geneproducts respectively, disengaging two of the more critical pathways involved in

cell cycle regulation {2788}. These HPV-positive oropharyngeal tumours composea distinct pathological entity with its ownclinical spectrum and basaloid morpholo-gy {888,1012,2072}, illustrating theemerging role of genetic characterizationas a potential means of determining prog-nosis and influencing management{1691}. Genetic evidence has clarified the vagueconcept of “field cancerization”. Most, ifnot all, multiple primary carcinomas of theupper aerodigestive tract derive from acommon clonal progenitor cell that under-goes a common early genetic alterations{187,2271}. Genetic evidence has helpedaccount for the perplexing problem oflocal tumour recurrence following seem-ingly complete tumour resection. In manyinstances, local tumour recurrencereflects extension of genetically damagedcells beyond the clinical and microscopicboundaries of carcinoma to the marginsof surgical resection {268,1626,1983,2777}.Microsatellite analysis of exfoliated cellsswabbed or rinsed from the oral cavity ofpatients with head and neck squamouscarcinomas consistently harbour geneticchanges that are identical to those in theprimary tumours, suggesting a non-inva-sive test for specific DNA-sequence vari-ants in saliva as a means of identifyingpatients with pre-invasive or invasive neo-plasms {2430}. Clonal genetic changesidentical to those found in primary headand neck SCC have been identified in cir-culating plasma or serum, suggesting amechanism for early cancer detectionand tumour surveillance {1853}. The useof highly sensitive genetic assays fordetecting rare cancer cells at the marginof tumour resection shows promise forpredicting the likelihood of tumour recur-rence {268,1983}.

Prognosis and predictive factors

Tumour size and nodal status are the mostsignificant prognostic factors {2060}.Histological grade correlates poorly withpatient outcome {1292,2195}. The valueof grading improves when only the deeplyinvasive margins of the tumour are evalu-ated {291,292,1927, 2818}. Tumoursinvading with pushing borders are lessaggressive than tumours showing a non-cohesive front showing diffuse spreadwith tiny strands or single cells.{1325,2132,2342,2653, 2841} Major riskfactors that adversely influence prognosis

BAFig. 4.12 A Verrucous carcinoma (VC) of the gingiva. B VC of the ginigva, spreading laterally to involve thecheek mucosa.

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are two or more positive regional nodes,extracapsular extension of nodal disease,or positive margins of resection {1429}.Other important histologic features asso-ciated with poor prognosis are tumourthickness and vascular invasion. Molecular markers with unequivocal prognostic and/or predictive significancehave not been identified {428,1052,1561,2106}.

Verrucous carcinoma

ICD-O code 8051/3

Although uncommon, 75% of all cases ofVC occur in the oral cavity. It is an exo-phytic, warty, slowly growing variant ofSCC with pushing margins. It typicallyinvolves older males {950,1251,1677,1695,2621}. Chronic smokeless tobaccouse is accepted as the primary etiologicalfactor for oral VC. Human papillomavirussubtypes 16 and 18 have been identifiedin up to 40% of oral VC {1927,2349}. OralVC begins as a well-demarcated, thinwhite keratotic plaque which quicklythickens and develops papillary (bluntedtips) or verruciform (pointed tips) surfaceprojections. Occasional lesions presentas erythaematous or pink papular mass-es. The colour depends on the amount ofkeratin produced and the degree of hostinflammatory response to the tumour. Thiscancer almost always remains broad-based or sessile and can become quiteextensive from lateral growth by the timeof diagnosis. Rare fungating examples,however, may appear to be somewhatpedunculated. Smokeless tobacco ker-atosis (tobacco pouch) is often seen onadjacent mucosal surfaces in patientswho chew tobacco or use snuff. Unlessthe tumour is infected or is encroachingon alveolar nerves in the jawbones, VC isan asymptomatic lesion. Surface ulcera-tion and haemorrhage are not seen,unless a focus of SCC is present in themass.VC consists of thickened club-shapedpapillae and blunt stromal invaginationsof well-differentiated squamous epitheli-um with marked keratinization. The squa-mous epithelium lacks the usual cytolog-ic criteria of malignancy, and by mor-phometry, the cells are larger than thoseseen in SCC {489}. Mitoses are rare, andobserved in the basal layers; DNA syn-thesis (S-phase) is also limited primarilyto the basal layers {737}. VC invades the

stroma with a pushing, rather than infil-trating border. Dense lymphoplasmacytichost response is common. Intraepithelialmicroabscesses are seen, and the abun-dant keratin may evoke a foreign bodyreaction. The surrounding mucosa shows progres-sive transition from hyperplasia to VC. Adownward dipping of epithelium often“cups” the VC periphery, and is the idealsite for deep biopsy {174,1192}. Withextensive surgical removal, and withoutneck dissection, the 5-year disease-freesurvival rate is 80-90%, although 8% ofpatients require at least one additionalsurgical procedure during that time{1870,1927}. Treatment failures usuallyoccur in patients with the most extensiveinvolvement or in those unable to tolerateextensive surgery because of unrelatedsystemic diseases. No molecular or othermarkers have yet shown prognostic sig-nificance for oral VC. However, one-fifthof these tumours contain a co-existingSCC which may not be identified withoutextensive histologic sectioning {1927}.Such hybrid tumours have a greater ten-dency to recur locally and a slight ten-dency to metastasize to the ipsilateralneck.

Basaloid squamous cell carcinoma

ICD-O code 8083/3

This is uncommon in the oral cavity,slightly more common in the oropharynx.It is described in the chapter on tumoursof the hypopharynx, larynx and trachea.

Papillary squamous cellcarcinoma ICD-O code 8052/3

This is rarely recognized in the oral cavi-ty and oropharynx other than as a com-ponent of a large SCC. It is described inthe chapter on tumours of the hypophar-ynx, larynx and trachea.

Spindle cell carcinoma

ICD-O code 8074/3

This unusual variant is more common inthe larynx than in the oral cavity andoropharynx, and is described in detail inthe chapter on tumours of the hypophar-ynx, larynx and trachea.

Acantholytic squamous cell carcinoma

ICD-O code 8075/3

The lip is the most frequent oral site.There are no distinguishing clinical signsand the microscopical features are con-sidered in the chapter on tumours of thehypopharynx, larynx and trachea. A vari-ant of this tumour has been referred to aspseudovascular SCC.

Adenosquamous carcinoma

ICD-O code 8560/3

In the oral cavity this is a SCC with clear-cut areas of adenocarcinoma, most fre-quently seen as a component of a largeSCC. It is described in the chapter ontumours of the hypopharynx, larynx andtrachea.

Carcinoma cuniculatum(epithelioma cuniculatum)

ICD-O code 8051/3

This rare variant of oral cancer has simi-larities to the lesion more commonlydescribed in the foot in which tumour infi-trates deeply into bone. The oral tumoursshow proliferation of stratified squamousepithelium in broad processes with ker-atin cores and keratin filled crypts whichseem to burrow into bone, but lack obvi-ous cytological features of malignancy{40}. Diagnosis on biopsy specimenscan be very difficult and correlation withthe clinical and radiographic features isrequired.

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Definition

Lymphoepithelial carcinoma (LEC) is apoorly differentiated squamous cell carci-noma (SCC) or undifferentiated carcino-ma, accompanied by a prominent reac-tive lymphoplasmacytic infiltrate. Themorphological features are indistinguish-able from those examples of nasopharyn-geal nonkeratinizing carcinoma with a richlymphoplasmacytic infiltrate.

ICD-O code 8082/3

Epidemiology

LEC is rare at these sites, and accountsfor 0.8-2% of all oral or oropharyngealcancers {1339,2741}. See Chapter 2.

Etiology

Epstein-Barr virus (EBV) has been testedin only a limited number of cases {819,856,1802,1875,2405}, but it appears thattumours occurring in Chinese are usuallypositive for EBV, while those occurring inCaucasians are usually negative. Theracial difference in the association withEBV is similar to LEC occurring in themajor salivary glands (see Chapter 5).

Clinical features

The patients present with an intra-oralmass, which may be ulcerated. Sometumours can be bilateral {801,2038}. Aproportion of patients present with neckmass due to regional lymph nodeinvolvement {119}.

Location and metastatic spread

More than 90% of all oral and oropharyn-geal LEC occur in the tonsil and tonguebase areas. The remaining cases arefound in the palate and buccal mucosa{444,694,2822}. The tumour has a highpropensity for regional cervical lymphnode involvement (approximately 70% ofcases at presentation) {119,444,1339}.Distant metastasis tends to occur in theliver and lung {119}.

Histopathology

LEC of the oral cavity and oropharynxshows morphologic features indistin-guishable from its nasopharyngeal andsinonasal counterparts. The surfaceepithelium is often intact. The tumour isinvasive, and comprises syncytial sheetsand clusters of carcinoma cells with

vesicular nuclei, prominent nucleoli andill-defined cell borders. A rich lympho-plasmacytic infiltrate is present within thetumour islands and the surronding stro-ma, which may appear desmoplastic.The tumour cells are immunoreactive forpan-cytokeratin and epithelial membraneantigen. EBV encoded RNA (EBER) hasbeen demonstrated by in-situ hybridiza-tion in oral / oropharyngeal LEC occur-ring in Chinese patients.


LEC of the oral cavity and oropharynx areradiosensitive, and in a high percentageof cases local control can be achievedeven in the presence of regional lymphnode metastasis {1339}. Local, regionaland distant failures occur in 3%, 5% and19% of cases respectively {444}. Distantmetastasis is associated with a poorprognosis.

Lymphoepithelial carcinoma W.Y.W. TsangJ.K.C. ChanW. Westra

Fig. 4.13 A Lymphoepithelial carcinoma of the tonsil. The tumour infiltrates beneath an intact surface epithelium. In this example, the tumour islands are obscuredby the heavy lymphoplasmacytic infiltrate. B Sheets and islands of tumour cells intimately admixed with lymphocytes and plasma cells. C Lymphoepithelial carci-noma of the palate. Carcinoma cells exhibit indistinct cell borders, pale chromatin and distinct nucleoli. Many lymphocytes are found among the carcinoma cells.

B CA

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177Epithelial precursor lesions

The pathologic assessment of precursorlesions is similar throughout the upperaerodigestive tract. It is described indetail in the Chapter 3 on tumours of thehypopharynx, larynx and trachea (page140).

Clinical features

The principal oral and oropharyngeallesions which may be precursor lesionsare white patches (leukoplakia) and redpatches (erythroplasia/erythroplakia) ormixed red and white lesions. The majori-ty of leukoplakias will not show dysplasiaand correspond to the hyperplasia cate-gory. Red and mixed lesions (speckledleukoplakia) show a higher frequency ofdysplasia, often of higher grade. Themajority of leukoplakias will not undergomalignant change and may even regressparticularly if apparent aetiologic factorsare removed.

Histopathology

The epithelium of precursor lesions maybe thick, but in the oral cavity it can alsobe atrophic. By definition, there is no evi-dence of invasion. The magnitude of sur-face keratinisation is of no importance. Allocation to categories within each ofthe classifications requires considerationfirstly of architectural features and then ofcytology.

HyperplasiaHyperplasia describes increased cellnumbers. This may be in the spinouslayer (acanthosis) and/or in thebasal/parabasal cell layers (progenitorcompartment), termed basal cell hyper-plasia. The architecture shows regularstratification without cellular atypia.

Dysplasia, / squamous intraepithelialneoplasia / atypical hyperplasia When architectural disturbance isaccompanied by cytologic atypia, theterm dysplasia applies. The terms squa-mous intraepithelial neoplasia (SIN) andatypical epithelial hyperplasia are usedsynonymously.There is a challenge in the recognition of

the earliest manifestations of dysplasiaand no single combination of the abovefeatures allows for consistent distinctionbetween hyperplasia and the earlieststages of dysplasia. Dysplasia is a spec-trum and no criteria exist to preciselydivide this spectrum into mild, moderateand severe categories.

Mild dysplasiaIn general architectural disturbance limit-ed to the lower third of the epitheliumaccompanied by cytological atypiadefine the minimum criteria of dysplasia.

Moderate dysplasiaArchitectural disturbance extending intothe middle third of the epithelium is theinitial criterion for recognizing this cate-gory. However, consideration of thedegree of cytologic atypia may requireupgrading.

Severe dysplasiaRecognition of severe dysplasia startswith greater than two thirds of the epithe-lium showing architectural disturbancewith associated cytologic atypia.However, as noted in the previous para-

Epithelial precursor lesions N. GaleB.Z. PilchD. SidranskyA. El Naggar

Table 4.01 Classification schemas that histologically categorize precursor and related lesions

2005 WHO Classification Squamous Intraepithelial Ljubljana Classification Neoplasia (SIN) Squamous Intraepithelial

Lesions (SIL)

Squamous cell hyperplasia Squamous cell (Simple) hyperplasia

Mild dysplasia SIN 1 Basal/parabasal cell hyperplasia*

Moderate dysplasia SIN 2 Atypical hyperplasia**

Severe dysplasia SIN 3*** Atypical hyperplasia**

Carcinoma in-situ SIN 3*** Carcinoma in-situ

* Basal/parabasal cell hyperplasia may histologically resemble mild dysplasia, but the former is conceptually benign lesion and the latter the lower grade of precursor lesions.

** ’Risky epithelium’. The analogy to moderate and severe dysplasia is approximate.*** The advocates of SIN combine severe dysplasia and carcinoma in-situ.

Table 4.02 Criteria used for diagnosing dysplasia

Architecture Cytology

Irregular epithelial stratification Abnormal variation in nuclear size (anisonucleosis)

Loss of polarity of basal cells Abnormal variation in nuclear shape (nuclear pleomorphism)

Drop-shaped rete ridges Abnormal variation in cell size (anisocytosis) Increased number of mitotic figures Abnormal variation in cell shape

(cellular pleomorphism)Abnormally superficial mitoses Increased nuclear-cytoplasmic ratioPremature keratinization in single cells Increased nuclear size (dyskeratosis)Keratin pearls within rete pegs Atypical mitotic figures

Increased number and size of nucleoli

W. WestraJ. Califano

N. JohnsonD.G. MacDonald

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creo


graph architectural disturbance extend-ing into the middle third of the epitheliumwith sufficient cytologic atypia is upgrad-ed from moderate to severe dysplasia.

Carcinoma in-situThe theoretical concept of carcinoma in-situ is that malignant transformation hasoccurred but invasion is not present. It isnot possible to recognize this morpholog-ically. The following is recommended forthe diagnosis of carcinoma in-situ: fullthickness or almost full thickness archi-tectural abnormalities in the viable cellularlayers accompanied by pronounced cyto-logic atypia. Atypical mitotic figures andabnormal superficial mitoses are com-monly seen in carcinoma in-situ.

Differential diagnosis

Reactive, regenerative or reparative squa-mous epithelium, for example in responseto trauma, inflammation, irradiation or

ulceration, may manifest atypical cytologyor architectural disturbance. Nutritionaldeficiencies such as iron, folate, and vita-min B12, can also simulate dysplasia.Such lesions are not considered precur-sor lesions and should be distinguishedfrom them. Clinical history is helpful andmorphological changes suggestive of theinciting event, such as ulceration, inflam-mation, haemorrhage, radiation-inducedmesenchymal and/or endothelial nuclearenlargement and hyperchromatism, maybe present. The epithelial changes inthese cases are generally less pro-nounced than in dysplasia. Relevance of dysplasia. It is reasonable toassume that the changes described indysplasia are due to genetic changes inthe epithelium occur, but it is unlikely thatthe mutations involved are the same onesas are associated with development ofmalignancy. More severe dysplasia hasbeen traditionally believed to be associat-

ed with a greater likelihood of progressionto malignancy. This might indicate that thegreater the accumulation of mutations intissue, the greater the chance that the crit-ical mutations for malignancy will be pres-ent. The corollary is also true in that malig-nancy can arise from non-dysplasticepithelium {2493} presumably becausethese critical mutations can be present inthe absence of the mutations causingdysplasia.

Genetics

There are no individual markers that reli-ably predict malignant transformation.The molecular biology techniques whichshow most promise as predictors ofdevelopment of SCC are large scalegenomic status (DNA ploidy) and loss ofheterozygosity (LOH) at defined loci{2286}.Dysplasia has been reported to be pres-ent in from 10-25% of leukoplakias

Table 4.03 Malignant transformation of oral leukoplakia (Reibel {2145})

Authors/Year Country Material Observation Cases with malignant(no. of cases) period (years) transformation (%)

Pindborg et al., 1968 {2049} Denmark 248 3.9 4.4Silverman and Rosen, 1968 {2362} USA 117 1-11 6.0Kramer et al., 1970 {1368} UK 187 - 4.8Mehta et al., 1972 {1699} India 117 10 0.9Silverman et al., 1976 {2358} India 4762 2 0.13Bánóczy, 1977 {118} Hungary 670 9.8 6.0Silverman et al., 1984 {2361} USA 257 7.2 17.5Lind, 1987 {1517} Norway 157 9.3 8.9Schepman et al., 1998 {2261} Netherlands 166 2.5 12.0

Fig. 4.14 A Acanthosis. Hyperplastic epithelium with thickened stratum spinosum. B Basal cell hyperplasia. Increase in progenitor compartment without dysplasia.C Mild dysplasia. Basal cell hyperplasia with relatively mild cytological change confined to lower third of epithelium.

B CA

creo

179Epithelial precursor lesions

{2286,2490}. Ploidy studies of dysplasticleukoplakias showed that the great major-ity of aneuploid lesions developed SCC inthe follow-up period, by contrast with 60%of tetraploid lesions and only about 3% ofdiploid lesions {2490}. No correlation wasfound between the degree of dysplasiaand DNA ploidy. Similar studies on ery-throplasias {2491} confirmed the high pre-dictive potential of aneuploidy in identify-

ing cases which progressed to SCC. Non-dysplastic white patches have also beenstudied {11} and although there was amuch lower incidence of malignant trans-formation, 80% of such cases were aneu-ploid.LOH studies have been undertaken con-trasting oral lesions which progressed toSCC or carcinoma in-situ during follow-upwith corresponding lesions which did not

progress. LOH on two chromosome arms,3p and 9p seemed to be particularlyimportant in predicting progression{2201}.

DC

BA

Fig. 4.15 A Moderate dysplasia. Drop shaped rete ridges, dysplasia extending to mid-third and moderate cytological changes B Severe dysplasia into upper thirdof epithelium with marked cytological change C Severe dysplasia into upper third of epithelium with prominent cytological change including abnormal mitoses.D Carcinoma in-situ. Abnormal cells seen throughout the full thickness of epithelium.


Definition

Proliferative verrucous leukoplakia (PVL)is a rare but distinctive high-risk clinicalform of oral precursor lesions. Because ofthe lack of specific histologic criteria, thediagnosis is based on combined clinicaland histopathologic evidence of progres-sion. Sequential biopsies show progres-sive dysplasia and the acquisition of aber-rant TP53 protein.

Clinical features

PVL is an aggressive form of oral leuko-plakia with considerable morbidity andstrong predilection to malignant transfor-mation {174,1005,1797,2360}. The etiolo-gy of this entity is unknown. The conditiondevelops initially as focal clinical hyperk-eratosis (leukoplakia) that progressivelybecomes a wide multifocal disease withgross exophytic features {174}. The aver-

age age at diagnosis is 62 years; womenare more commonly afflicted (ratio, 4:1).Typically, multiple oral sites are affected.The most common site in women is thebuccal mucosa and the tongue in men.Carcinoma develops after a protractedperiod of time. The most common sites ofthe carcinoma are gingiva and tongue.PVL is characterized by high recurrencerate and histological progression. Manycases are resistant to all forms of treat-ment, including laser microsurgery, surgi-cal excision and radio-and chemotherapy.Conservative management of theselesions has been unsuccessful and widesurgical excision is the best hope for con-trol.

Other precancerous conditions

Precancerous conditions (PCs) are gener-alized clinical states associated with a

significantly increased risk for SCC.Epithelial atrophy, increased mitotic activ-ity and impaired epithelial repair mecha-nisms are fundamental to PCs of differentetiology.

Iron deficiencyOriginally described in the context ofsideropenic dysphagia, it is an importantcause of epithelial atrophy. The associa-tion of iron deficiency with oropharyngealsquamous cell carcinomas has beenobserved since the mid-thirties of the 20thcentury {21}. However, a significantdecrease of cases with hypopharyngealcancers and iron deficiency was noted inSweden in the seventies {1433}. Fewcases of oral cancer and iron deficiencyhave been published in the last 20 years.

Proliferative verrucous leukoplakia and

precancerous conditions

A.K. El Naggar P.A. Reichart

DC

A

Fig. 4.16 Proliferative verrucous leukoplakia (PVL) A Extensive, thick, white plaques. B Hyperplasia and dense hyperkeratosis of early PVL. C Histology from a clin-ical case of PVL showing verrucous surface with hyperkeratosis, hypergranulosis and a dense inflammatory infiltrate in the corium. D Same case as shown on fig.C two years later showing more florid verrucous hyperplasia illustrating the progressive nature of the condition.

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181Proliferative verrucous leukoplakia

Oral lichen planusOLP is a chronic mucocutaneous immuneinflammatory condition. Malig nant trans-formation is still controversial {639,2359};one review reporting malignant transfor-mation rates between 0% and 5.6%{2116}. The controversy is due to lack of uniform

clinical and histological criteria for OLPand oral lichenoid lesions (OLL). The lat-ter have also been termed interfacemucositis or lichenoid mucositis. Orallichenoid lesions have been consideredby some to represent the lesion at risk ifassociated with dysplasia. In a recentstudy {2664} it was shown that all cases ofmalignant transformation (1.7%) involvedcases of OLL and not OLP. Similarly, astudy {2896} investigating whether OLPwithout dysplasia is premalignant byusing microsatellite analysis for loss ofheterozygosity (chromosomes 3p, 9p,17p) did not support OLP as a lesion atrisk.However, until distinct clinical and histo-logical criteria have been developed onhow to differentiate OLP from OLL, bothlesions have to be considered as ‘at riskfor malignant transformation’.

Oral submucous fibrosis (OSF)This chronic, progressive condition of theoral mucosa {2115} is etiologically strong-ly associated with the chewing of arecanut which has recently been categorizedby IARC as a human carcinogen {1}. It isalmost exclusively seen in ethnic groupsusing areca nut alone or as a componentof betel quid.Clinically there is mucosal rigidity of vary-ing intensity due to fibroelastic transfor-mation of the juxtaepithelial connectivetissue. Fibrous bands and mucosal pallorare characteristic {498}. Histologically,there is epithelial atrophy, keratosis anddysplasia in up to 25% of cases {498}. Ina population-based prospective study, inIndia, SCC developed in 7% of patientswith OSF over a period of 17 years {1798}.

SyphilisLate stage (tertiary) syphilis associatedwith leukoplakia had a high risk of malig-nancy, but this is now largely of historicalinterest {1721}.

Xeroderma pigmentosumThis is a rare neurocutaneous diseasewith an autosomal-recessive mode ofinheritance. The syndrome is caused bydeficient nucleotide excision repairmechanisms {2090}. The skin, includingthe lips, is affected and shows epithelialatrophy and hyperpigmentation. Patientsare extremely sensitive to light and showan increased predisposition to UV-asso-ciated malignancies of the skin.Carcinomas of the tongue have also

been described {1306,1994,2704}.

Lupus erythematosusThis is a chronic autoimmune disease ofunknown etiology. Carcinomas, mainly ofthe lips, have been described in affectedindividuals {2264,2696}.

Epidermolysis bullosa dystrophicans(Hallopeau-Siemens type)This disease of the skin and oral mucosahas an autosomal dominant pattern ofinheritance. Oral leukoplakia and occa-sional cases of SCC have been observedin association with epidermolysis bullosa{226,2288}.

Fig. 4.20 Oral submucous fibrosis with a broadband of subepithelial collagenous tissue.

Fig. 4.18 Erythroplasia / erythroplakia associatedwith oral lichen planus (precancer).

Fig. 4.19 Syphilis. Interstitial glossitis due to latestage syphilis with squamous cell carcinoma at theleft tip of the tongue (Collection of J.J. Pindborg,M.D., Copenhagen).

Fig. 4.17 Sideropenic dysphagia. Iron deficiencyanaemia with depapillated tongue, depigmentationof the upper lip and epithelial erosion of the lowerlip.

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Definition

These form a range of localised hyper-plastic exophytic and polypoid lesions ofhyperplastic epithelium with a verrucousor cauliflower-like morphology. Lesions offibroepithelial hyperplasia are not gener-ally included. Not every papilloma canbe allocated to one of the diagnostic cat-egories described below.

ICD-O code 8050/0

Epidemiology

Papillomas are common, with a preva-lence of approximately 0.1%-0.5% {94,1342,2569}.

Etiology

HPV infection causes some papillomas{2076} and at least types 1,2,3,4,6,7,10,11,13,16,18,30,31,32,33,35,38,45,52,55,57,59,69,72,73 sequences have beendetected in benign oral lesions.Clinically, latent HPV is common in oralmucosa and HPV DNA sequences canbe detected in over 80% of individuals.There is no absolute associationbetween the virus type and the type ofpapilloma {866} though focal epithelialhyperplasia is almost exclusively associ-ated with types 13 and 32. HPV infectionof oral tissue may be transmitted hori-zontally, including venereally, perinatallyand possibly in utero {2518}.

Histopathology

Histological differential diagnosis for alltypes includes lesions of fibroepithelialhyperplasia: fibroepithelial polyps,fibrous epulis and papillary hyperplasiaassociated with candidal infection ordentures. These have a more prominentfibrous component and no viral change.Verruciform xanthoma is a solitary lesionwith a very similar clinical and histologi-cal presentation.Extensive multiple papillomas or diffusepapillomatous change raise the possibil-ities of HPV lesions in immunosuppres-sion, acanthosis nigricans, naevus uniuset lateris, focal dermal hypoplasia,Cowden syndrome, papillary and verru-

cous dysplastic lesions and papillarysquamous {2488} or verrucous carcino-ma. Florid oral papillomatosis is a clinicalterm for diffuse papillomatous change ofthe mucosa for which no specific causecan be identified and is not a definedclinico-pathological entity.

Squamous cell papilloma and

verruca vulgaris

Definition

A benign, hyperplastic wart-like localisedproliferation of the oral epithelium {2076}.

Epidemiology

Squamous papillomas are common inchildren and in adults in the 3rd to 5thdecades but may be found at any age.There is an almost equal sex incidencewith a slight male predominance.

Etiology

Evidence of causative HPV infection canbe found in less than half of oral squa-mous papillomas {866,2516,2747}, andthese lesions are the intraoral counter-part of verruca vulgaris. Many HPV sub-types have been detected including2,4,6,7,10,40. The presence of HPV viri-on components ultrastructurally andimmunocytochemically indicates activeviral replication in the lesion. Virus trans-mission appears to be mostly horizontalor by autoinoculation. Lesions in childrentend to arise at anterior oral sites and thesource of infection is often verruca vul-garis on the skin, particularly on the fin-gers. Infectivity is low. The remainder of squamous papillomasare of unknown etiology. HPV sequencesmay be detected by PCR but the signifi-cance of this is unclear.

Papillomas E.W. Odell

DCFig. 4.21 Papilloma. A Typical papillary structure of squamous papilloma. This example is only lightly kera-tinised and negative for papilloma virus on immunocytochemistry. B Papilloma from the vermillion bordershowing extensive keratinisation. Note the inwardly facing rete ridges at the periphery. C Moderately ker-atinised papilloma of verruca vulgaris type showing koilocytic change in the upper prickle cell layers. DStrong and extensive staining for papilloma virus in a flat papilloma from an HIV infected individual. Thereis widespread infection in the upper prickle cell layer but the architecture of the epithelium is little changed.Note the sharp lesion margin on the left.

BA

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183Papillomas

Localization

Any oral site may be affected but the mostcommon are the hard and soft palate,labial mucosa, tongue and gingiva.

Clinical features

Squamous papillomas are soft, peduncu-lated lesions formed by a cluster of fin-ger-like fronds or a sessile, dome-shaped lesion with a nodular, papillary orverrucous surface. The surface may bewhite or of normal mucosal colourdepending on the degree of keratiniza-tion {2076}. Lesions are usually singlebut fairly frequently multiple, particularlyin children and for verruca vulgaris.Squamous papillomas grow rapidly overa period of a few months to a maximumof about 6mm diameter and then remaina constant size.

Histopathology

Lesions are exophytic and comprisefolds of hyperplastic stratified epitheliumthat are usually thickly para- or orthoker-atinized but may be non keratinised.Squamous papillomas associated withHPV (oral verruca vulgaris) comprise acluster of finger-like projections from anarrow base, each with a sharp kera-tinised tip, supported on ramifying coresof connective tissue containing dilatedcapillaries. Stratification of the epitheliumis well ordered. Mitoses may be frequentand there may be mild anisonucleosisconsistent with hyperplasia, but no atyp-ia. The fronds are thickly keratinised,often with a prominent keratohyalinelayer of large coarse granules. Small fociof HPV-infected cells (koilocytes) canusually be found in the upper prickle celllayer. These keratinocytes have crum-pled, darkly stained nuclei with perinu-clear haloes but appear very similar tovacuolated keratinocytes that are com-mon in the normal oral mucosa.Koilocytes may be more frequent in earlylesions. Less frequently, viral inclusionsare found. Rete processes at the baseoften turn inwards and are symmetrical.Small foci of lymphocytic inflammationmay lie in the fronds or at the base butinflammation is usually sparse unless thelesion is subject to trauma or other irrita-tion {4,1929}. HPV may be identified byimmunocytochemistry or in-situ hybridis-ation but this is not necessary for diag-nosis {2076}. Papillomas without detectable activeHPV replication show more variation.

They may appear identical to verrucavulgaris but without koilocytes or promi-nent keratohyaline granules, or formrounded broad-based dome shapedlesions similar to condyloma. The hyper-plastic epithelium may form papillaryexophytic fronds or arborising reteprocesses. Some are flat zones of acan-thotic hyperplastic epithelium withincreased numbers of dermal papillaesimilar to plane warts of the skin.


Oral verruca vulgaris may regress spon-taneously, particularly in children, butresponds to simple excision or ablationby laser or cryosurgery. Recurrence isunusual provided all lesional tissue isremoved and there is no malignantpotential.

Condyloma acuminatum

Definition

Oral counterpart of anogenital condylo-ma acuminatum

Synonyms

Venereal wart; venereal condyloma

Epidemiology

Lesions are usually diagnosed betweenthe mid 2nd and 5th decade with a peakin teenagers and young adults {2916}.

Etiology

Epithelial infection by HPV, most com-monly types 6,11,16 and 18 though oth-ers have been detected {700,1380}.Transmission is usually venereal or byautoinnoculation from concomitant geni-tal lesions {1975}.Histological appearance is not an accu-rate indicator of a genital origin.

Localization

Most lesions arise on the labial mucosa,tongue and palate in anterior oral sitesthough any area may be affected {700,2916}.

Clinical features

Condylomas are painless, rounded,dome-shaped exophytic nodules up to15 mm in diameter, larger than squa-mous papillomas and verruca vulgaris.They have a broad base and a nodular ormulberry-like surface that is slightly red,pink or of normal mucosal colour.Lesions may be multiple and are thenusually clustered {2076,2916}.

Histopathology

Condylomas are similar to squamouspapillomas but with short blunt roundedfronds of hyperplastic epithelium of evenlength forming a smooth or nodular, flator rounded surface. Keratin is usuallyabsent or sparse, occasional examplesshow moderate keratin and are whiteclinically. Between the folds, crypts orclefts lined by epithelium extend close tothe broad base and may be filled withkeratin debris in keratinised lesions.Clusters of koilocytes identical to thosedescribed above are much commonerthan in squamous papillomas and areusually a prominent feature. Unlike squa-mous papilloma, rete processes are bul-bous and short, of even length and donot curve inwards {700,2076}.


Condyloma acuminatum often respondsto simple excision or ablation by laser orcryosurgery but appears to carry a high-er risk of recurrence than squamouspapilloma. Unlike ano-genital condylo-ma, there is no documented risk of malig-nant transformation, regardless of thepresence of high-risk HPV types.

AFig. 4.22 Condyloma acuminatum. A Several sessile, cauliflower-like swellings forming a cluster. B Typicalpapilloma structure in condyloma showing the more rounded architecture in comparison with verruca vul-garis. Note a verrucous area on the left; many of these lesions have features of both types of papilloma.

B

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Condyloma acuminatum in children rais-es the possibility of sexual abuse, butnon-sexual transmission is possible{1380} and probably frequent.

Papillomas and papillomatosis

in immunodeficiency

More florid presentations of HPV-inducedlesions are found in immunosuppression,particularly in HIV infection. Lesions maybe larger, multiple and coalesce to formextensive patches of affected mucosa.Occasionally the entire oral mucosa maybecome papillomatous and some ofthese presentations are not easily classi-fied. Unusual HPV subtypes and multipleHPV subtypes are more frequent inimmunosuppression. Occasional lesionsin HIV infection are dysplastic and are ofuncertain malignant potential.

Focal epithelial hyperplasia

Definition

Multiple oral papillomas induced by HPV13 and 32

Synonym

Heck disease

Epidemiology

This is primarily a disease of children,adolescents and young adults. Originallydescribed in Inuit and native Americans{69} but now recognised worldwide. Thecondition is endemic in some countriesand prevalence may be as high as 40%of children in localised areas {94,332,1014}.

Etiology

Infection by HPV types 13 and 32.

Localization

All areas of the oral cavity may be affect-ed but the lesions are most common onthe labial and buccal mucosa and thetongue {69,332,1014}.

Clinical features

Typically there are multiple asympto-matic lesions, each a soft rounded or flatplaque-like sessile swelling with a slight-ly nodular surface. They are usually pinkin colour or sometimes white, and 2-10mm in diameter. Lesions develop inclusters or confluent patches {332}.

Individual lesions may appear and dis-appear during the course of the disease{1014}.

Histopathology

The histological features are more dis-tinctive than squamous papilloma orcondyloma. Each lesion is a slightlyraised or rounded sessile swellingformed by a sharply demarcated zone ofepithelial acanthosis, similar to condylo-ma acuminatum but with a less promi-nent papillomatous structure. The bulk oflesion is formed by exophytic acanthosis,without formation of well-defined projec-tions of epithelium and the lesion con-tains minimal connective tissue papillae.Koilocytes similar to those of squamouspapilloma are usually present and, inaddition, there are usually characteristic“mitosoid bodies”, which are nuclei withcoarse clumped heterochromatin resem-bling a mitotic figure. Mitosoid bodies arecharacteristic but not specific for focalepithelial hyperplasia. The base of the

lesion is flat and level with the adjacentepithelium without rete process enlarge-ment {332,2076}. HPV may be detectedon immunocytochemistry or by in-situhybridisation but this is not necessary fordiagnosis if the clinical presentation istypical {2076}.

Genetic susceptibility

Familial clustering and endemic areasmay result from horizontal transmission.


The condition appears to resolve sponta-neously after a period of years and israrely found in adults. It has no malignantpotential.

Fig. 4.23 Focal epithelial hyperplasia. Typical clinical appearance of multiple papillomatous nodules.

Fig. 4.24 Focal epithelial hyperplasia, viral change and mitosoid body (inset).

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185Granular cell tumours

Definition

A benign tumour of soft tissues whichmost often arises in the tongue and isthought to be of Schwann cell origin. It iscomposed of a poorly demarcated accu-mulation of plump granular cells whichare often intimately associated withskeletal muscle.

ICD-O code 9580/0

Synonym

Granular cell myoblastoma

Epidemiology

Granular cell tumours are rare.Approximately 50% of all lesions arise inthe head and neck and over half of theseare found in the tongue. They arise in allage groups, with a peak between 40 and60 years. In about 10-20% of patients thelesions are multiple. Females are affect-ed more often than males with an M/Fratio of 2:1.

Etiology

No etiological factors are known. Thelesion is thought to arise from Schwanncells. The granularity may be a senes-cent change associated with accumula-tion of lysosomes.

Localization

Granular cell tumours may arise in theskin, soft tissues, breast and lungs, butover 50% involve the head and neck andthe tongue is the most common singlesite. Oral lesions may also be found inthe buccal mucosa, floor of oral cavity orpalate. Lesions may be multiple, affect-ing more than one intraoral site, or involv-ing oral and extraoral sites {477}. Rarelesions have been reported in the sali-vary glands {331}.

Clinical features

The lesion typically presents as asmooth, sessile mucosal swelling 1-2 cmin diameter with a firm texture. The over-lying epithelium is of normal colour ormay be slightly pale. Occasionally thereis candidal infestation of the superficial

epithelium and the lesion may then pres-ent as a discrete, white plaque.

Macroscopy

Tumours are usually 1-2 cm in diameterwith a smooth surface. The cut surfaceshows a poorly demarcated lesion whichis pale yellow or cream and firm on cut-ting.

Histopathology

The lesion is composed of plumpeosinophilic cells with central small darknuclei and abundant granular cytoplasm.The cells may be polygonal or elongatedand have indistinct cell membranes,often giving the impression of a syn-cytium. The lesion is not encapsulatedand the granular cells extend into adja-cent tissues, typically skeletal muscle,

where they appear to merge with musclecells {477,2791}. Granular cells extendup to the epithelium, often forming smallislands in the connective tissue papillae.The granules stain positively with period-ic acid Schiff (PAS).A characteristic feature of granular celltumour is that in up to 30% of cases theoverlying epithelium shows pseudoep-itheliomatous hyperplasia that may bemisdiagnosed as carcinoma.

ImmunoprofileThe lesion is strongly and uniformly pos-itive for S-100 protein. Cells also expressneurone-specific enolase, calretinin,inhibin-alpha and PGP 9.5, and show finegranular cytoplasmic positivity for thelysosome related antigen CD68 {764,2791}.


Granular cell tumours are benign andrarely recur, even after conservativeremoval. Occasional lesions havebehaved aggressively and malignantgranular cell tumours have beendescribed.

Granular cell tumour P.M. Speight

Fig. 4.25 Granular cell tumour. The typical presen-tation of granular cell tumour: a sessile swelling onthe tongue covered by normal appearing epitheli-um.

BAFig. 4.26 Granular cell tumour. A Prominent pseudoepitheliomatous hyperplasia of the oral epithelium over-lying a granular cell tumour. B The pseudoepitheliomatous hyperplasia can be mistaken for carcinoma, butcareful examination shows eosinophilic granular cells in the connective tisues.

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DC

BA

Fig. 4.27 Granular cell tumour. A The granular cells frequently extend close to the overlying epithelium, but do not fuse with it. B The granular cells infiltrate wide-ly and often appear to merge with striated muscle cells. C The granules are PAS positive (Periodic acid Schiff stain). D The granular cells are strongly and uni-formly positive for S-100 protein.

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187Keratoacanthoma

Definition

Keratoacanthoma is a benign tumourthat is believed to arise from the epitheli-um of hair follicles.

ICD-O code 8071/1

Synonyms

Molluscum sebaceum, molluscumpseudocarcinomatosum, self-healing pri-mary squamous carcinoma, tumour-likekeratosis, idiopathic cutaneous pseudo-epitheliomatous hyperplasia.

Epidemiology

Keratoacanthoma occurs more often inwhites, and is almost twice as frequent inmen as in women. Although they havebeen seen in infants, keratoacanthomasare rare in persons under 20 years of ageand the peak incidence is between thesixth and seventh decade {881}.

Etiology

Interestingly, the uptake of carcinogens(e.g. via particular smoking habits) maybe relevant in human tumours {641}. Noother risk factors are known. The conceptof a common viral origin (papillomavirus-es), popular for some years, has beenabandoned. In addition to the solitary type, clinicalvariants with multiple keratoacanthomashave been described, sometimes with aunilateral distribution {881}. Genetic fac-tors may be involved in these cases, forfamilial clustering occurs, with multiplekeratoacanthomas in affected individu-als.

Localization

Keratoacanthomas preferentially occuron sun exposed hairy skin {881}. Thus,they are frequent on the skin of the face,including the lips (8% of cases), andextremely rare at hairless sites. Whetheror not a “true keratoacanthoma” of theoral mucosa exists or not remains contro-versial {1929}. However, a small numberof cases of the solitary form have beenreported in intraoral sites {414,973}, andmucocutaneous linings may also be

affected in the generalized forms (e.g.the Ferguson-Smith, Grzybowski andWitten and Zak types) {881}.

Clinical features

Keratoacanthoma is characterised byrapid growth followed by slow, sponta-neous involution over several months{881}. Exact figures about regressiontime, however, are difficult to obtain,since the common mode of treatment isexcision. The mature lesion is usuallybud- or dome-shaped and is brownish orslightly reddish. Over time a central ker-atinous crater appears at the expense ofthe surrounding softer tumour tissue untilfinally a cup- or saucer-shape lesiondevelops that appears ulcerated, but is,in fact, lined by tumour epithelium andoften covered with horn masses. An erup-tive variant can be distinguished which ismultifocal and often lacks the central ker-atin-filled crater. Following trauma and/orinfection, true ulceration may occur,especially in areas like the lips, probablydue to repeated scratching or biting. Inthe oral cavity, the above-described phe-notypes rarely occur. Instead, the puta-

tive oral lesion mimics a broad spectrumof pseudoneoplastic and neoplasticlesions {1929}.

Macroscopy

The basic gross features of epidermallesions have been already described.However, such prototypic lesions arerarely seen in the oral cavity. Instead, asin cases at the inner side of the vulva andwithin the anal canal, oral keratoacan-thomas present as verrucous, speckledor even ulcerated lesions. Also, they mayproduce deep projections, which canextend through minor salivary glands andreach the surface of underlying bone.

Histopathology

Keratoacanthomas show a verrucoussurface, and underneath keratinizedclefts and penetrating squamous reteprocesses are found with deep keratinpearls. Atypia is minimal, and mitotic fig-ures are rare or absent. Dense inflamma-tory infiltrates, including granulocytestypically are found in the adjacent stromaand within the deep parts of the tumour,so that the margins seem ill defined. The

Keratoacanthoma T. LöningK.T. Jäkel

Fig. 4.28 Keratoacanthoma of the mucosal aspect of the upper lip with the cup-shape margin on the right,and the keratin-filled crater that is in the centre of the lesion on the left.

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hallmark of keratoacanthoma is the over-all architecture, with a cup-shapedappearance and a collar-like circumfer-ence.A major diagnostic problem arises whendestructive infiltration takes place as hasbeen reported, including some cases inyoung individuals. When this kind oftumour growth occurs in the elderly, it isof course extremely difficult or evenimpossible to distinguish the lesion fromcarcinoma, particularly from carcinomacuniculatum, which also shows minimalatypia despite its destructive growth pat-tern {1929}.

Histogenesis

A large body of evidence exists pertain-ing to the histogenesis of keratoacan-thomas {881}. In fact, it is their origin frompilosebaceous follicles which has leadsome authors to deny the existence ofintraoral keratoacanthomas {1929}. Thisstandpoint may be acceptable for sites

of the oral cavity where pilo-sebaceousrudiments are rarely seen (e.g. gingiva).However, there are also cases reportedin areas such as the buccal mucosa,which is a preferential site for the ectopicsebaceous glands (Fordyce spots). Inaddition, as also suggested for skinlesions, preprogrammed progenitor cellsof the most superficial (intraepidermal)parts of the pilosebaceous unit may besufficient as a source of (intraoral) kera-toacanthoma.


Epidermal keratoacanthomas are clearlybenign lesions {881}. However, for similartumours of the external openings (oralcavity, vulva, anal canal) there are no reli-able data, since these lesions areextremely rare, present diagnostic prob-lems and therefore are usually complete-ly excised. Recurrences after surgicalexcision do not occur.

Fig. 4.29 Keratoacanthoma. A Intraoral keratoacanthoma with a marginal lip and a cup-shaped lesion, in this case with parakeratotic keratin, and the typical denseinflammatory infiltrate at the epithelial-stromal interface. B The higher magnification reveals the inflammatory infiltrate in detail, and the absence of cellular atyp-ia in the lesional epithelium.

BA

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189Papillary hyperplasia

Median rhomboid glossitis E.W. Odell

Papillary hyperplasia is an asymptomaticnodular or papillary mucosal lesion typi-cally seen in the palate of patients whowear dentures. Most patients wear ill-fit-ting dentures, wear dentures continuous-ly {2645} or have poor denture hygiene.Lesions also arise in non-denture wear-ers, in xerostomia or individuals with ahigh arched palate. Florid and extensivepresentations occur in immunosuppres-sion {937} and HIV infection {2150}.There is sessile nodular papillomatoushyperplasia of epithelium and supportingunderlying fibrous tissue. There is usual-ly parakeratinisation or less frequentlyorthokeratinisation. Rete processes are

usually rounded or sharply defined at thebase of the lesion but there may be pseu-doepitheliomatous hyperplasia with ker-atin pearls and a poorly defined deepmargin. Differential diagnosis includesdiffuse HPV-induced papillomatosis,periorificial plasmacytosis {937} and ver-ruciform xanthoma. Other multinodularlesions such as focal epithelial hyperpla-sia, acanthosis nigricans and Cowdensyndrome appear similar histologicallybut have distinctive clinical presenta-tions.

Papillary hyperplasia E.W. Odell

Fig. 4.30 Papillary hyperplasia. Low power viewshowing the overall architecture with nodularfibroepithelial hyperplasia and apparentlydetached islands of epithelium in the upper corium.Inflammation is slight in this example but dependson candidal infection and whether a denture over-lies the lesion. It may be a very prominent feature.

Median rhomboid glossitis typicallyforms a patch of papillary atrophy nearthe midline of the dorsum of the tongueat the junction of the anterior two thirdsand posterior third in the region of theembryological foramen caecum. It is nolonger thought to be a developmentaldefect but the result of chronic candidalinfection {719,2825}.The epithelium lacks papillae, and shows

psoriasiform hyperplasia and sometimesareas of pseudoepitheliomatous hyper-plasia. A mild degree of atypia may bepresent. Fungal hyphae are present inthe superficial epithelium but are usuallysparse and revealed only in multiple sec-tions. Scarring and nodularity persistafter antifungal treatment. Differentialdiagnosis is aided by knowledge of thespecific site and includes reactive

fibroepithelial hyperplasia, granular celltumour and other nodular lesions of thetongue. Occasionally the lesion can bedifficult to differentiate from squamouscell carcinoma {931, 1932}, particularlywhen hyperplasia is extensive andepithelial processes reach or penetratethe underlying muscle.

Fig. 4.31 Median rhomboid glossitis. A Two lesions of chronic candidiasis of the median rhomboid glossitis form. That on the left is flat and more typical, that onthe right more nodular and irregular. B Typical median rhomboid glossitis with active candidal infection showing long bulbous rete hyperplasia and suprapapillaryatrophy. Note the broad band of dense fibrosis separating the inflamed superficial corium from the underlying muscle.

BA

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Epidemiology

Tumours of the oral cavity and orophar-ynx account for 9-23% of all salivarygland neoplasms in major series {669,704,2301}. The most common sites arethe palate (44-58%), lips (15-22%) andbuccal mucosa (12-15%) {669,704,2301,2711}. Variations in these series probablyreflect patterns of referral in differentinstitutions, together with geographicaland ethnic differences. Tumours of the oropharynx are relativelyuncommon and form only 1.1-3.3% of allminor gland tumours {669,704,2448}.Most studies show a female to male ratioin the range of 1.2:1-1.5:1 {2711}.

Location

Nearly half of all oral and oropharyngealsalivary tumours are malignant, and insome sites, such as the lower lip, tongueand floor of the oral cavity, the largemajority are carcinomas.. It is interestingto note that while 80-90% of labial sali-vary gland tumours involve the upper lip,there is a 3-5x greater risk of neoplasmsin the lower lip being malignant {400,669,704, 1871,1963}.Most of the principle types of salivarygland tumour have been reported in theoral cavity. In some tumours such ascanalicular adenoma, duct adenomasand polymorphous low-grade adenocar-cinoma, the minor glands are by far themost frequent site of involvement.Whether there are genuine cases of intra-oral Warthin tumour, or whether reportedexamples represent oncocytic hyperpla-sia and metaplasia with reactive lympho-cytic infiltration, is contentious {2669}.

Salivary gland carcinomas

ICD-O codes

Acinic cell carcinoma 8550/3Mucoepidermoid carcinoma

8430/3Adenoid cystic carcinoma

8200/3Polymorphous low-grade adenocarcinoma 8525/3Epithelial-myoepithelial carcinoma 8562/3 Clear cell carcinoma, NOS 8310/3 Basal cell adenocarcinoma 8147/3Cystadenocarcinoma 8450/3Mucinous adenocarcinoma

8480/3Oncocytic carcinoma 8290/3Salivary duct carcinoma 8500/3Myoepithelial carcinoma 8982/3Carcinoma ex pleomorphicadenoma 8941/3

Acinic cell carcinomaThese are uncommon in minor glands {9,280,340,410,734,864,2886} and form 2-6.5% of all intraoral salivary glandtumours {669,704,2711}. In one series,the age range was from 11-77 years, witha mean of 45 years, and a male to femaleratio of 1.5:1 {2711}. The most commonsites are the buccal mucosa, upper lipand palate where the tumours usuallyform non-descript swellings. The micro-scopical features are similar to those inmajor glands. However, in one seriesthere appeared to be more areas con-sisting of solid sheets of epithelium withsecretory material and fewer areas show-

ing ductal differentiation in tumours from

the minor glands {2711}.

Mucoepidermoid carcinoma This most common malignant salivarygland tumour involves minor glands, andaccounts for 9.5-23% of all minor glandtumours {669,704,2711}. About half ofthe cases arise in the palate and othercommon sites include the buccalmucosa, lips, floor of oral cavity andretromolar pad. They appear to be muchmore frequent in the lower lip than theupper lip {1871}. The tumour is often asymptomatic anddetected during a routine dental exami-nation. Many appear as bluish, domedswellings that resemble mucoceles orhaemangiomas. Less commonly, the sur-face appears granular or papillary.Tumours of the base of tongue ororopharynx may cause dysphagia andsublingual tumours can lead to anky-loglossia and dysphonia. High-gradetumours are uncommon but can result inulceration, loosening of teeth, paraesthe-sia or anaesthesia. Mucoepidermoid car-cinoma is the most common salivarygland tumour to develop in a centrallocation within the bone of the mandibleor, less frequently, the maxilla {280}.The microscopical features of minorgland mucoepidermoid carcinomas arethe same as those seen in the majorglands.

Adenoid cystic carcinoma This lesion is relatively common in theminor glands. In the AFIP series 42.5% ofall adenoid cystic carcinomas were inminor glands and 20.5% of the total was

in the palate {669}. Other sites included

Salivary gland tumours J.W. Eveson

Table 4.04 Percentage of malignant minor salivary gland tumours in different sites in published series.

Upper Lip Lower Lip Lip NOS Palate Tongue Cheek Retro-molar FOM* Tonsil Other

Auclair et al {669} 22.5 60.2 17.2 46.8 85.7 50.5 89.7 88.2 41.4 65.6

Waldron et al {2711} 14 86 - 42 - 46 91 80 - 69

Eveson & Cawson {704} - - 14.8 47 91.7 50 33.3 - 50 -

* Floor of the mouth

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191Salivary gland carcinomas

the tongue, tonsil and oropharynx,cheek, lips, retromolar pad and gingiva{899}. They are much more frequent inthe upper lip than the lower lip{669,1871,2711}. Intraoral adenoid cys-tic carcinomas usually present as slowgrowing submucosal masses and ulcera-tion may be seen, particularly in thepalate. Pain, or evidence of nerveinvolvement, is usually only present inadvanced tumours. Most tumours showthe typical cylindromatous or cribriformvariant microscopically, but some mayhave tubular areas and a few are pre-dominantly solid {2711}.

Polymorphous low-grade adenocarcinoma This tumour is seen almost exclusively inminor glands and is considered in detailin Chapter 5.

Epithelial-myoepithelial carcinoma This tumour is rare in minor glands andthe literature consists mainly of singlecases or short series {154,436,493,784,981,992,1177}. Tumours of the oral cavi-ty and oropharynx formed only 10.3% ofthe AFIP series {669}. The palate is themost common site. The clinical presenta-tion is non-specific and the microscopi-cal features are the same as those inmajor glands.

Basal cell adenocarcinomaThis tumour is rare in minor glands. Therewere none in the AFIP series {669} but

there have been isolated case reports{563,785,1211,1540,2059,2703}. Themost common sites are the palate, buc-cal mucosa and lip. They usually formasymptomatic, smooth or lobulated sub-mucosal masses apart from one casethat presented with dull pain andinflamed overlying mucosa {2703}.Microscopically they are similar to basalcell adenocarcinomas of the majorglands.

CystadenocarcinomaThese tumours are uncommon and about32% developed in the minor glandswhere they are frequently papillary{411,790}. The most frequent sites arethe palate, lips, buccal mucosa, tongue{1834} and retromolar regions. They areusually slow growing and painless butsome palatal tumours have eroded theunderlying bone and invaded thesinonasal complex. This tumour is con-sidered in detail in Chapter 5.

Oncocytic carcinomaThis tuomur is rare and there were onlytwo cases involving the oral cavity in theAFIP series of 26 cases {669}. One wasin the palate and the other the buccalmucosa. Reported cases also include anadditional case in the palate {274} andthe AFIP case from the buccal mucosa{922}. The microscopical features areconsidered in Chapter 5.

Salivary duct carcinomaThis tumour is rare in minor salivaryglands. A recent review documented 20cases {1147} and a further 6 cases havebeen reported {1559,2673}. The mostcommon location was the palate (65%).Other sites included the buccal mucosaand vestibule (19%), tongue (8%), retro-molar pad (4%) and upper lip (4%). Theage range was 23-80 years (mean 56years). Some tumours formed painlessswellings but many in the palate werepainful and ulcerated or fungated. Therewere metastases to regional lymph nodesin 25% of cases and this was associatedwith a poor prognosis. The range ofmicroscopical appearances was similarto that seen in the major glands.

Myoepithelial carcinoma This is a rare salivary gland tumour and26% of cases in a review of the literature(9 cases) involved the oral cavity ororopharynx {668} and only isolated caseshave been published since this review{1827}. The most common location is thepalate. The clinical signs and symptomsare non-specific and the microscopicalfeatures are considered in Chapter 5.

Carcinoma ex pleomorphic adenomaLesions involving the oral and oropharyn-geal minor glands formed 17.5% of theAFIP series {669}. 63% of cases were inthe palate and 10.5% were in the upperlip. There were no cases in the lower lip.Other sites included the tongue, buccal

Fig. 4.32 A Mucoepidermoid carcinoma. Low power showing low-grade tumour with both cystic and solid areas and an inflamed, fibrous stroma. B Adenoid cys-tic carcinoma. This predominantly solid variant shows peri- and intraneural invasion. C Salivary duct carcinoma with large, somewhat oncocytic cells, cribriformareas, small papillae and comedo-type necrosis.

B CA

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mucosa and tonsil/oropharynx. Theyusually form a painless mass of longduration and there may be a history ofrecent rapid growth, often with ulcera-tion. The microscopical features are sim-ilar to those of major glands.

Mucinous adenocarcinoma is very rarewhile clear cell carcinoma is a controversialentity; both are discussed in Chapter 5.

Salivary gland adenomas

ICD-O codes

Pleomorphic adenoma 8940/0Myoepithelioma 8982/0Basal cell adenoma 8147/0Canalicular adenoma 8149/0Duct papilloma 8503/0Cystadenoma 8440/0

Pleomorphic adenomaThese amount to 40-70% of minor glandtumours, the large majority of casesbeing located in the palate, lips andbuccal mucosa {2711}. They usuallypresent as painless, slow-growing, sub-mucosal masses, but occasionally theyare traumatised and bleed or ulcerate.They rarely exceed 3 sphere cm in diam-

eter. Oral pleomorphic adenomas aresimilar microscopically to tumours else-where but frequently lack encapsulation,especially in the palate. They tend to becellular, and hyaline or plasmacytoid celltypes are common. Squamous metapla-sia is also frequently seen and may beextensive. Some tumours have a striking-ly lipomatous stroma and this should notbe misinterpreted as tumour invading fat.Cases of intraoral pleomorphic adenomawith florid pseudoepitheliomatous hyper-plasia of the overlying mucosa havebeen reported following incisional biopsy{2541}.

MyoepitheliomaThe minor glands are the common sitefor and myoepitheliomas account forabout 42% of all of these tumours. Twothirds of the intraoral cases involve thepalate {899}. They show the same rangeof morphological variation described inChapter 5, but predominantly plasmacy-toid tumours have a predilection for thepalate of younger individuals {546}.

Basal cell adenomaAbout 20% of basal cell adenomasinvolve the oral cavity and the upper lipand buccal mucosa are the most com-mon sites {669}. They are histologicallysimilar to those in major glands.

CystadenomaThese lesions are uncommon and form7% of benign minor gland tumours {668}.Of these, 30% arose in the lips, 23% inthe cheek, 20% in the palate and 26% inother oral and oropharyngeal sites.Clinically they resemble mucoceles andrarely exceed 1cm in diameter. Thepathology is discussed in Chapter 5.

Canalicular adenoma and duct papillo-mas arise almost exclusively in the minorsalivary glands and are discussed indetail in Chapter 5.

Fig. 4.33 Pleomorphic adenoma which started atpalate involving the mid face and entire oral cavity.

DCFig. 4.34 A Pleomorphic adenoma. Tumour presenting as a firm swelling on the lateral aspect of the junc-tion between the hard and soft palate. B Plasmacytoid, or hyaline myoepithelial cells are often a conspic-uous feature of pleomorphic adenomas of minor glands. C Tumors may have an abundant lipomatous com-ponent that is occasionally misinterpreted as invasion. D Multifocal adenomatosis. Both basal cell adeno-ma and canalicular adenoma can show multifocal tumours and evidence of duct transformation within sali-vary gland lobules.

BA

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193Kaposi sarcoma

Definition

Kaposi sarcoma (KS) is a locally aggres-sive tumour that typically presents withcutaneous lesions in the form of multiplepatches, plaques or nodules but mayalso involve mucosal sites, lymph nodesand visceral organs. The disease is uni-formly associated with human herpesvirus 8 (HHV-8) infection. KS rarelymetastasizes and belongs to the groupof intermediate type vascular tumours.

ICD-O code 9140/3

Epidemiology

Four different clinical and epidemiologi-cal forms of KS are recognized: 1. clas-sic indolent form occurring predominant-ly in elderly men of Mediterranean/EastEuropean descent, 2. endemic AfricanKS that occurs in middle-aged adultsand children in Equatorial Africa who arenot HIV infected, 3. iatrogenic KSappearing in solid organ transplantrecipients treated with immunosuppres-sive therapy and also in patients treatedby immunosuppressive agents, notablycorticosteroids, for various diseases{2629}, 4. acquired immunodeficiencysyndrome-associated KS (AIDS KS), themost aggressive form of the disease,found in HIV-1 infected individuals, that isparticularly frequent in homo- and bisex-ual men. The relative risk of acquiring KS

in the latter patients is > 10,000 {909}; ithas been reduced with the advent ofhighly active antiretroviral therapy(HAART) {212}, although this has notbeen proven yet for oral KS {1993,2120}.

Etiology

The disease is the result of a complexinterplay of HHV-8 with immunologic,genetic, and environmental factors {392}.Oral exposure to infectious saliva seemsto be a potential risk factor for the acqui-sition of HHV-8 {1995}. HHV-8 is found inKS cells of all epidemiological-clinicalforms of the disease {2242} and isdetected in the peripheral blood beforethe development of KS. Nevertheless, ithas been observed that a declined inci-dence of KS did not appear to be causedby a decline in HHV-8 transmission{1959}.

Localization

The most typical site of involvement byKS is the skin, particularly of the face andlower extremities. During the course ofthe disease or initially, mucosal mem-branes such as oral mucosa, lymphnodes and visceral organs may beaffected, sometimes without skin involve-ment. Oral KS most frequently occurs onthe palate, followed by the gingiva andthe tongue.

Clinical features

Classic type of KS is characterized by theappearance of purplish, reddish blue ordark brown macules, plaques and nod-ules that may ulcerate. They are particu-larly frequent in distal extremities and maybe accompanied by lymphoedema. Thedisease is usually indolent, lymph nodeand visceral involvement occurs infre-quently. Classic KS may be associatedwith haematolymphoid malignancies.In the endemic form of KS, the diseasemay be localized to skin and shows a pro-tracted course. A variant of endemic dis-ease, a lymphadenopathic form in Africanchildren is rapidly progressive and highlylethal.Iatrogenic KS is relatively frequent. Itdevelops in a few months to several yearsafter the transplantation of solid organs orimmunosuppressive treatment for a vari-

Kaposi sarcoma I. van der WaalJ. LamovecS. Knuutila

Table 4.05 Epidemiological-clinical types of Kaposi sarcoma

From: WHO Classification of Tumours of Soft Tissue and Bone {775}.

Type Risk groups Skin lesions Visceral involvement Course-predilection sites

Classic Elderly men of Mediterranean/ Lower legs Rare IndolentEast European descent

Endemic Middles-aged men and children Extremities Fairly common - adults Indolent - adultsin Equatorial Africa Frequent - children (lymph nodes) Aggressive - children

Iatrogenic Immunosuppressed patients Lower legs Fairly common Indolent or aggressive (post-transplant, other diseases)

AIDS-associated Younger, mainly homo- and Face, genitalia, Frequent Aggressive bisexual HIV-1 infected men lower extremities

Fig. 4.35 Kaposi sarcoma of the palate.

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ety of conditions. The disease mayresolve entirely upon withdrawal ofimmunosuppressive treatment althoughimmunosuppressive treatment althoughits course is somewhat unpredictable.AIDS-related KS is the most aggressivetype of KS. Early oral KS is represented bysolitary or multiple red or bluish flatlesions, while the later stage is character-ized by a nodular, sometimes massiveappearance with or without secondaryulceration.

Histopathology

Microscopic features of all four differentepidemiological-clinical types of KS donot differ. Early lesions of the skin or themucosa are uncharacteristic and presentwith subtle vascular proliferation {2216}.In the patch stage, vascular spaces areincreased in number, of irregular shape,and may dissect collagen fibres in thesuperficial corium. They often run parallelto the epithelium. The vascular prolifera-tion is often perivascular and periadnexal.Endothelial cells lining the spaces are flat-tened or more oval, with little atypia. Pre-existing blood vessels may protrude intothe lumen of new vessels. Admixed aresparse lymphocytes and plasma cells;frequently, extravasated erythrocytes anddeposits of hemosiderin surround the vas-

cular structures. Slits lined by attenuatedendothelial cells between collagen bun-dles are also seen. In some cases, thereis a proliferation of spindle or ovalendothelial cells around pre-existingblood vessels in the dermis or submu-cosa. Slit-like spaces, lymphocyte andplasma cell infiltration and extravasatederythrocytes are also observed.In plaque stage, all characteristics ofpatch stage are exaggerated. There ismore extensive angio-proliferation withvascular spaces showing jagged outlines.Inflammatory infiltrate is denser andextravascular red cells and siderophagesare numerous. Hyaline globules (likelyrepresenting destroyed red blood cells)are frequently found.Nodular stage is characterized by well-defined nodules of intersecting fasciclesof spindle cells with only mild atypia andnumerous slit-like spaces containing redcells. Peripherally, there are ectatic bloodvessels. Many spindle cells show mitoses.Hyaline globules are present inside andoutside the spindle cells. Some patients,usually with endemic nodular type KS,develop lesions that closely resemblelymphangioma.The main differential diagnosis includesKaposiform haemangioendothelioma{775}.

ImmunoprofileThe lining cells of clearly developed vas-cular structures are usually positive forvascular markers, while the spindle cellsconsistently show positive reaction forCD34 and commonly for CD31 but arefactor VIII negative. All cases, irrespectiveof epidemiologic subgroup, are HHV-8positive. The new marker FLI1, a nucleartranscription factor, appears to beexpressed in almost 100% of differentvascular tumours, including KS {780}.


The evolution of disease depends on theepidemiological-clinical type of KS and onits clinical extent. It is also modified bytreatment that includes surgery, radio-and chemotherapy. Patients with oral KSwho did not receive triple antiretroviraltherapy had a higher death rate thanthose having exclusively cutaneous mani-festations of the disease {2192}.

Fig. 4.36 Kaposi sarcoma. A Inflammatory-like aspect of palatal Kaposi sarcoma. B Vascular slits and sparsely distributed lymphocytes.

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195Lymphangioma of the tongue

Definition

A benign, cavernous/cystic vascularlesion composed of dilated lymphaticchannels.

ICD-O code 9170/0

Epidemiology

Lymphangiomas are common paediatriclesions, which most often present at birthor during the first years of life.Lymphangiomas appear mostly in thehead and neck area but may be found inany other part of the body.

Etiology

Early or even congenital appearance inlife and lesional architecture are in favourof a developmental malformation, withgenetic abnormalities playing an addi-tional role in cystic lymphangioma of theneck in association with Turner syndrome{416}.

Clinical features

The lesion presents as a somewhat cir-cumscribed painless swelling, which issoft and fluctuant on palpation. In oralinvolvement, the tongue is the site ofpredilection, the majority of lymphan-giomas being located on the dorsal sur-face of the anterior part of the tongue.The size may vary from pinhead dimen-sions to massive lesions involving theentire tongue and surrounding struc-tures. The typical lymphangioma of the

tongue is characterized by irregularnodularity of the dorsum of the tonguewith grey and pink, grapelike projections.Secondary haemorrhage in lymphan-giomas is not a rare occurrence. CT scanreveals homogeneous non-enhancingareas {775}.A staging system of lymphatic malforma-tions of the head and neck based on theanatomic location has shown to be of rel-evance in predicting prognosis and out-come of surgical intervention {561,991}.

Macroscopy

Lymphangiomas form a multicystic orspongy mass, the cavities of which con-tain watery to milky fluid.

Histopathology

Lymphangiomas are characterized bythin-walled, dilated lymphatic vessels ofdifferent size, which are lined by a flat-

tened endothelium. There is no encapsu-lation. The lumina may be either empty orcontain proteinaceous fluid, lymphocytesand sometimes a few erythrocytes.Longstanding lesions show interstitialfibrosis.

ImmunoprofileThe endothelium demonstrates variableexpression of FVIII-rAg, CD31 and CD34{781}.

Electron microscopy

The endothelium of thin-walled vessels isnot enveloped by a basement membraneand no pericytes are attached to it, thusdirectly contacting with the interstitium.With increasing calibre the vessels mayacquire pericytes and smooth muscle,respectively.


Recurrences are due to incompleteremoval. Current interest is centred ontreating these lesions with sclerosingagents {2117}, interferon {1953} orbleomycin {2903A}. Malignant transfor-mation does not occur. There is anexceedingly rare case report of a squa-mous cell carcinoma arising in a lym-phangioma of the tongue {203}.

Lymphangioma I. van der Waal

Fig. 4.37 Lymphangioma on the dorsum of thetongue.

Fig. 4.38 Lymphangioma. A Cavernous lymphangioma. B Flattened endothelial lining in lymphangioma.

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Definition

A benign ectomesenchymal chondromyx-oid tumour that arises in the anteriortongue.

Epidemiology

In 1995, nineteen cases of the previouslyundescribed entity were reported. Eversince, a few additional case reports havebeen published {1169}. The reported agerange varies from 9-78 years; there is nodistinct sex predilection.

Clinical features

Most tumours presented as an otherwiseasymptomatic, slow growing solitary nod-ule in the anterior dorsal tongue. The con-sistency may vary from firm to soft elastic.

Macroscopy

The cut surface has a gelatinous consis-tency with occasional foci of haemor-rhage.

Histopathology

The tumour is usually well-circumscribed,but not encapsulated. Occasionally, mus-cle fibres and nerve branches may beentrapped within the tumour. It is com-posed of round, cup-shaped, fusiform, orpolygonal cells with uniform small nucleiand moderate amounts of faintlybasophilic cytoplasm; some tumours mayshow nuclear pleomorphism, hyperchro-

matism, and multinucleation, while mitoticfigures are scarce {2410}. In addition, thepresence of myxoglobulosis-like changeshas been reported {1169}. Alcian bluestains at pH 0.4 and 2.5 are positive, whilemucicarmine is usually faintly positive inthe extracellular matrix. The tumour cellsdo not stain with the periodic acid-Shiff(PAS). In the histological differential diag-nosis other myxoid and chondroid lesionsshould be excluded, such as focal oralmucinosis, the mucous retention phenom-enon, soft-tissue myxoma, nerve sheathmyxoma, myxomatous changes in fibrouslesions, chondrosarcoma, chondroid cho-ristoma, and variants of pleomorphic ade-noma or myoepithelioma arising fromminor salivary glands.

ImmunoprofileReactivity with polyclonal and monoclonalanti glial fibrillary acidic protein (GFAP) ispositive in almost all reported cases;reactivity with anti-cytokeratin monoclonalantibody has been positive in the majorityof cases as well, while variable stainingresults were observed for S-100, CD57and smooth muscle actin {2410}.

Histogenesis

The tumour cells are possibly derivedfrom undifferentiated ectomesenchymalprogenitor cells that have migrated fromthe neural crest {2410}.


Surgical excision is the treatment ofchoice. The recurrence rate is apparentlylow.

Ectomesenchymal chondromyxoid

tumour of the anterior tongue

I. van der Waal

Fig. 4.39 Ectomesenchymal chondromyxoid tumourof the anterior tongue presenting as a small nodule.

Fig. 4.40 A Rather well demarcated ectomesenchymal chondromyxoid tumour. B Net-like pattern of round or ovoid cells in a chondromyxoid background.

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197Focal oral mucinosis

Definition

Focal oral mucinosis (FOM) is the oralcounterpart of focal cutaneous muci-nosis and cutaneous myxoid cyst. It ispostulated that FOM develops as theresult of a fibroblastic overproduction ofhyaluronic acid due to an unknowncause {2615}.

Epidemiology

Today, fewer than fifty cases have beenreported. The lesion may occur at allages, but it is rare in children {906}.There is no distinct sex predilection.

Clinical features

The clinical presentation is usually that ofan otherwise asymptomatic fibrous orcystic-like lesion. The most common siteis the gingiva; less common sites includethe palate, cheek mucosa and tongue.The consistency may vary from soft elas-tic to firm.

Histopathology

The histopathology is characterized by awell-circumscribed area of myxomatoustissue in which fusiform or stellate fibrob-lasts are present {299}. Reticular fibresare sparse or absent. The mucinousmaterial shows alcianophilia at pH 2.5.The histologic differential diagnosisincludes soft-tissue myxoma, myxoma-tous change in fibrous lesions, nerve

sheath myxoma, and mucous retentionphenomenon. The lack of reticular fibresand the sharp delineation distinguishesFOM both from soft-tissue myxoma andfrom myxomatous changes in fibrouslesions {2615}. Nerve sheath myxomausually shows a lobular architecture and,conspicuously, contains numerous mastcells. The mucous retention phenomenonis surrounded by a wall of granulation tis-

sue or an epithelium-lined wall, while themucoid material contains histiocyticcells; such features are lacking in FOM.


The lesion is treated by conservative sur-gical excision and has no tendency torecur.

Focal oral mucinosis I. van der Waal

Fig. 4.41 Focal oral mucinosis. Fibroma-likeswelling of the cheek mucosa based on focal oralmucinosis.

Fig. 4.42 Focal oral mucinosis. A Well-demarcated area of myxomatous connective tissue. B Delicate fib-rillar processes extending from fibroblast cytoplasm.

B

A

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Definition

A benign tumour arising from the alveolarridges of newborns and composed ofnests of cells with granular cytoplasm setin a prominent vasculature {2744}.

Synonym

Congenital epulis of the newborn

Epidemiology

In a review of the literature 216 caseshave been collected since its firstdescription in 1871. Females are affectedten times more often than males {2152}.

Clinical features

Congenital granular cell epulis (CGCE)occurs twice as often in the maxilla as inthe mandible, usually presenting as asolitary, somewhat pedunculated fibro-ma-like lesion attached to the alveolarridge near the midline. A few cases ofsimultaneous occurrence of a CGCE anda granular cell tumour of the tongue havebeen reported {1564,2848}. The size of aCGCE may vary from a few millimetres upto several centimetres.Since the availability of ultrasound exam-ination techniques, a number of caseshave been diagnosed in the prenatalstage {1839,2000}.

Histopathology

CGCE consists of large, slightlyeosinophilic cells with granular cytoplasmset in a prominent vasculature. There isno cellular or nuclear pleomorphism, andmitotic activity is not usually observed.The presence of odontogenic epitheliumscattered throughout the lesions hasbeen reported. Immuno histochemically,the tumour cells are positive for vimentinand neuron specific enolase; there is noreactivity with cytokeratin, CEA, desmin,hormone receptors or S-100 {1968}.Pseudoe pi theliomatous changes in theoverlying epithelium, although common inthe granular cell tumour, do not occur inCGCE. An extre mely rare case of a

congenital leiomyomatous epulis hasbeen reported {2542}.

Histogenesis

The histogenesis is unknown. The lack ofimmunoreactivity with S-100 protein sug-gests that the tumour is derived from acell line different from granular celltumour. Furthermore, the hypothesis of anon-neoplastic lesion can be raised.


Spontaneous regression may occur, butsurgical removal is usually indicated dueto interference with feeding or respiration.The tumour has no tendency to recurafter surgery.

Congenital granular cell epulis I. van der Waal

Fig. 4.43 Congenital granular cell epulis of the max-illa.

Fig. 4.44 Congenital granular cell epulis. A Slightly eosinophilic cells with granular cytoplasm in a prominent vasculature. B Absence of nuclear and cellular pleo-morphism.

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199Haematolymphoid tumours

Non-Hodgkin lymphoma

Definition

Non-Hodgkin lymphomas (NHL) of theoral cavity and oropharynx are defined aslymphoid cell neoplasms in which the bulkof the disease occurs in the palate,tongue, floor of mouth, gingiva, buccalmucosa, lips, palatine tonsils, lingual ton-sils or oropharynx.

ICD-O codes

Diffuse large B-cell lymphoma(DLBCL) 9680/3Mantle cell lymphoma 9673/3Follicular lymphoma 9690/3Extranodal marginal zone B-cell lym-phoma of MALT type 9699/3Burkitt lymphoma 9687/3T-cell lymphoma (including anaplasticlarge cell lymphoma) 9714/3

Epidemiology

Although NHL is the second most com-

mon cancer of the oral cavity, it onlyaccounts for 3.5% of all oral malignancies{683}. NHL of the oral cavity and orophar-ynx account for 13% of all primary extran-odal NHL, with approximately 70% ofthese occurring in the tonsils {809}. Theyaffect patients over a wide age range(including children), but most patients arein the 6th and 7th decades. Burkitt lym-phomas occur predominantly in childrenand young adults. Patients with an under-lying immunodeficiency state (e.g. HIVInfection) are also usually younger.

Etiology

There is no known etiology in mostpatients. A minority of patients have anunderlying immunodeficiency state (e.g.HIV infection, post-transplantation), which predisposes to the development ofNHL. There is a strong association withEpstein-Barr virus (EBV) for lymphomasoccurring in the setting of immunodefi-ciency as well as in extranodal NK/T cell

lymphoma of nasal-type {371,962,1476,2850}. Extranodal marginal zone B-celllymphoma of MALT type may be associat-ed with Sjögren syndrome {2476}.

Localization

The palatine tonsil is the most frequentlyinvolved site, followed by palate, gingivaand tongue {683,809,1476,2532}.

Clinical features

Patients with NHL of the lip, buccalmucosa, gingiva, floor of mouth, tongueor palate usually present with ulcer,swelling, discoloration, pain, paraesthe-sia, anaesthesia, or loose teeth. Thosewith NHL of the Waldeyer ring (tonsils) ororopharynx usually present with a sensa-tion of fullness of the throat, sore throat,dysphagia, or snoring. The high-gradetumours often show rapid growth.Systemic symptoms such as fever andnight sweat are uncommon {201}. Clinical examination reveals solitary ormultiple lesions, in the form of an exo-phytic mass, ulcer or localized swelling.Some cases may mimic inflammatory

Haematolymphoid tumours A.C.L. ChanJ.K.C. Chan

Fig. 4.45 A Primary large B cell lymphoma of the lip. The mucosa shows a diffuse infiltrate of lymphoma cellsbeneath an intact stratified squamous epithelium. B Primary large B cell lymphoma of the tongue. In thisexample, the mucosa is partly ulcerated.

BA

Table 4.06 Frequency of the various types of pri-mary lymphoma of the tonsil {1704}

Diffuse large B-cell lymphoma 64%(DLBCL) ICD-O code 9680/3

Mantle cell lymphoma 10%ICD-O code 9673/3

Follicular lymphoma 8%ICD-O code 9690/3

Extranodal marginal zone 6.5%B-cell lymphoma of MALT type* ICD-O code 9699/3

T-cell lymphoma (including 6.5%anaplastic large cell lymphomaICD-O code 9714/3)

Burkitt lymphoma 5%ICD-O code 9687/3

* Reported as monocytoid B-cell lymphoma andimmunocytoma in the original series.

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conditions, such as periodontitis.Tonsillar lymphoma usually manifests asasymmetric tonsil enlargement, althoughthe disease can be bilateral in up to 9%of cases {2250}. The regional lymphnodes can be enlarged as a result of lym-phoma involvement or reactive changessecondary to ulceration.


Three-quarters of patients have localizeddisease, with or without accompanyingcervical lymph node involvement at pres-entation (Stage IE/IIE). Patients with lym-phoma of the tonsil are prone tometachronous or synchronous gastroin-testinal tract involvement, suggesting ahoming mechanism among differentmucosal sites {1998,2139,2250}.

Histopathology

Most NHL of the oral cavity and orophar-ynx are of B-cell lineage, with DLBCLbeing the commonest (>50%) {370,1476,1704,2142,2530}. The surface stratifiedsquamous epithelium is either intact orulcerated. The stroma is densely infiltrat-ed by lymphoma cells, which vary inappearance depending on the histologic

type. In the tonsil, not uncommonly thereare some residual lymphoid follicles dueto incomplete involvement of the tissue.

Diffuse large B-cell lymphoma (DLBCL)DLBCL is characterized by large to medi-um-sized cells which may resemble cen-troblasts. Nuclear multilobation is promi-nent in some cases. There can be areasof coagulative necrosis. In DLBCL of thetonsils, a focal follicular pattern may bepresent {2138}, and it has been arguedthat the follicles result from colonization ofpre-existing follicles rather than de novoneoplastic follicle formation. In somecases, there may be an associated com-ponent of extranodal marginal zone B-cell lymphoma of MALT type or follicularlymphoma, indicating that the DLBCLrepresents high-grade transformation ofthe latter {1998}.

Mantle cell lymphomaLymphoma cells are usually monotonous,and frequently have small irregularnuclei, dense chromatin and scanty cyto-plasm. They may show a mantle zone dis-tribution around residual follicles. Rarecases can have a blastic appearance

and are associated with a higher prolifer-ation rate {19}.

Follicular lymphoma Follicular lymphoma is characterized byfollicles that frequently lack polarity andmantle zone. The neoplastic follicles con-sist of a mixture of centrocytes and cen-troblasts, often without accompanyingtingible-body macrophages.

Extranodal marginal zone B-cell lym-phomas of MALT type These lymphomas most often involve thetonsil, and less commonly the palate, gin-giva, buccal mucosa, tongue and lip{295,962,1476,1507,1629,1998,2225,2531}. The surface epithelium is oftenintact. In a background of reactive lym-phoid follicles, there is an interfollicularand perifollicular infiltrate of small tomedium-sized cells with roundish orindented nuclei. Some cells have a mod-erate amount of clear cytoplasm, resem-bling monocytoid B-cells. There can beclusters of admixed plasma cells.Follicular colonization can be seen insome cases. A distinctive feature is inva-sion of the epithelial component (e.g. sur-

B CAFig. 4.46 Primary large B cell lymphoma of the oral cavity and oropharynx: cytological spectrum. A Large cells with predominantly round nuclei and membrane-bound nucleoli, consistent with centroblastic morphology. B Predominantly medium-sized cells with abundant pale cytoplasm. C Large cells with round or multi-lobated nuclei.

B CAFig. 4.47 Primary large B cell lymphoma of the tonsil with focal follicular features. A The left field shows the predominant component of diffuse large cell lymphoma.The minor component with follicles is shown in the right field. B The diffuse large B cell lymphoma component comprises large cells effacing the normal architec-ture of the tonsil. C Focally, there are follicles comprising a monotonous population of large cells. It is unclear whether this represents a grade 3 follicular lymphomawith diffuse large B cell lymphoma, or a diffuse large B-cell lymphoma with follicular colonization.

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face or crypt epithelium, minor salivaryglands), forming lymphoepithelial lesions.

Burkitt lymphomaThere is typically a starry sky pattern cre-ated by interspersed histiocytes. Thelymphoma cells appear monotonous andmedium-sized, with coarse chromatin,multiple small nucleoli and a smallamount of basophilic cytoplasm. The cel-lular outline usually appears squared off.Frequent mitotic figures and apoptoticbodies are constant features.

Immunoprofile. B-cell lymphomasexpress pan-B markers such as CD19,CD20, CD22 and CD79a. Some DLBCLscan express CD10 and/or BCL6. Withinthe group of low-grade B-cell lym-phomas, follicular lymphoma is charac-terized by CD10 and BCL6 expression,

mantle cell lymphoma CD5 and cyclin D1expression, and extranodal marginalzone B-cell lymphoma none of thesemarkers. Bcl-2 Immunoreactivity is help-ful for distinction of follicular lymphomafrom reactive follicular hyperplasia.

Extranodal NK/T cell lymphoma of nasal-type Extranodal NK/T cell lymphoma of nasal-type can present primarily as an intraoraltumour in the palate, tonsil, oropharynx orlip {371,2639}. Please refer to the sectionof ‘non-Hodgkin lymphoma’ in ‘Tumoursof the nasal cavity and paranasal sinuses’for details.

T-cell lymphomas Peripheral T-cell lymphomas, includinganaplastic large cell lymphomas, canoccasionally involve the oral cavity

{1476,2200,2530}. Some anaplastic largecell lymphomas (CD30+ T-cell lympho-proliferative disorder) of the oral cavitycan regress spontaneously {760}. HTLV-1-associated adult T-celllymphoma/leukaemia may also presentas NHL of the Waldeyer ring {2616}.

Immunodeficiency-associatedlymphomasThe lymphomas that develop in the oralcavity of patients with HIV infection aremost commonly DLBCL with frequentEBV association (75%) {962,2141},although EBV-associated T-cell lym-phomas have also been reported in thissetting {1476,2589}. A distinctive form ofDLBCL, plasmablastic lymphoma, hasrecently been shown to exhibit apredilection for the oral cavity of HIV-pos-itive subjects. It differs from the usual

Haematolymphoid tumours

Fig. 4.48 Extranodal NK/T cell lymphoma of the palate. A The mucosa, which is densely infiltrated by lymphoma cells, shows ulceration. B The lymphoma cellscomprise small, medium-sized and large cells with irregular nuclear foldings.

BA

Fig. 4.49 Immunodeficiency-associated lymphoproliferative disorders. A Post-transplant lymphoproliferative disorder, plasmacytic hyperplasia, involving tonsil. BPlasmablastic lymphoma of the oral cavity in HIV-positive subject. The cells possess slightly eccentrically-located large vesicular nuclei, prominent nucleoli, andamphophilic cytoplasm.

BA

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DLBCL by the plasmablastic morpholo-gy, frequent lack of expression of CD45and the pan-B marker CD20, andexpression of plasma cell-associatedmarkers (e.g. VS38c and CD138) {576}.EBV is identified in 60% of cases.Histologically, the tumour shows a starry-sky appearance and a high proliferationindex. The large tumour cells haveeccentric vesicular nuclei, central promi-nent nucleoli, abundant basophilic cyto-plasm and paranuclear hof. There is nomaturation into plasma cells. Post-transplant lymphoproliferative disor-der (PTLD) can also affect the oral cavi-ty, and they are frequently associatedwith EBV (>80%). The ‘early’ lesions,including plasmacytic hyperplasia andinfectious mononucleosis-like PTLD,commonly involve the tonsils of childrenor younger adults {355,356,2830}. Thearchitecture of the tonsil is preserved,with expansion of the interfollicular areasby small lymphocytes, polyclonal plasmacells, plasmablasts and immunoblasts.Clonal immunoglobulin gene rearrange-ment is rare {355,2830}. Most lesionsregress with reduction in immunosup-pression, but rare cases may progress topolymorphic PTLD {2830}. Polymorphicand monomorphic PTLD can also pres-ent in the oral cavity (e.g. tonsil, gingiva,alveolus): the former shows architecturaleffacement, necrosis, cytologic atypiatogether with a full range of B-cell matu-ration, while the latter is indistinguishablefrom conventional DLBCL, and less com-monly Burkitt lymphoma {1301,1926,2131,2850}. Clonal immunoglobulin generearrangement is frequently demonstrat-ed in polymorphic and monomorphicPTLD. Regression after reduction inimmunosuppression may still be possiblein some cases of polymorphic PTLD, butprogression is usually the rule formonomorphic PTLD. (Please refer to‘Post-transplant lymphoproliferative dis-orders’ in ‘WHO classification of tumours:Tumours of haematopoietic and lym-phoid tissues’ for details).

Differential diagnoses

In infectious mononucleosis, the tonsilsmay appear histologically worrisome,with necrosis, partial effacement of archi-tecture, and striking immunoblastic prolif-eration, mimicking DLBCL {431}. In con-trast to the latter, there is usually a spec-trum of lymphoid cells in different stagesof differentiation and activation

(immunoblasts, plasmablasts and plas-ma cells). On immunostaining, the largecells usually consist of a mixture of B- andT-cells, and there is no immunoglobulinlight chain restriction. As a rule of thumb,infectious mononucleosis has to be seri-ously excluded before making a diagno-sis of DLBCL in young patients. Some cases of DLBCL (especially thosein the tonsil) can exhibit deceptivelycohesive growth and a sharp interfacewith the uninvolved mucosa, closely mim-icking poorly differentiated carcinoma ormalignant melanoma. Marked irregularnuclear foldings and amphophilic cyto-plasm, if present, should point moretowards a diagnosis of lymphoma.Appropriate immunostains can readilysolve this diagnostic problem.Anaplastic plasmacytoma can be difficultto distinguish from DLBCL, including theplasmablastic variant. An important clueto the diagnosis is the presence ofcoarsely clumped ‘clock-face’ chromatinin the few differentiated cells that arepresent. There are often intermingledatypical plasma cells. There is usually noassociation with EBV. A prior history ofmultiple myeloma, if present, would be astrong point to substantiate a diagnosisof plasmacytoma. Extramedullary myeloid sarcoma (granu-locytic sarcoma) is commonly misdiag-nosed as large cell lymphoma. The cluesto diagnosis are the fine chromatin, pres-ence of cytoplasmic eosinophilic gran-ules in some cells, and interspersedeosinophilic myelocytes. The diagnosiscan be confirmed by immunoreactivity formyeloid or monocytic markers (e.g.myeloperoxidase, CD13, CD33, CD117,neutrophil elastase, lysozyme, CD68).

The differential diagnosis between extra-nodal marginal zone B-cell lymphoma ofMALT type in the tonsil and reactive lym-phoid hyperplasia can be extremely diffi-cult, because of the presence of reactivelymphoid follicles, minimal atypia of thelymphoid cells in the former and pres-ence of numerous plasma cells.Furthermore, lymphoepithelial lesions inthe tonsil are difficult to assess since thetonsillar epithelium is normally extensive-ly infiltrated by small lymphoid cells. Thefollowing features would favour a diagno-sis of lymphoma: lymphoid cells infiltrat-ing beyond the fibrous band at the baseof the tonsil, presence of sheets ofCD20+ B-cells between the lymphoid fol-licles, immunoglobulin light chain restric-tion, and molecular evidence of clonalimmunoglobulin gene rearrangement. Some extranodal NK/T cell lymphomas ofnasal-type comprise predominantly smalllymphoid cells with minimal atypia, ren-dering it difficult to distinguish from areactive lymphoid infiltrate. Histologicclues to the diagnosis are the extensivenecrosis and angiocentric growth.Demonstration of sheets of CD56+ orEBER+ cells would strongly support thediagnosis.There is some morphologic overlap ofanaplastic large cell lymphoma witheosinophilic ulcer (traumatic eosinophilicgranuloma; atypical histiocytic granulo-ma) {645,674,701}, which is character-ized by a rich inflammatory infiltrate(especially eosinophils) and occasionallarge cells {760}. Anaplastic large celllymphoma can be distinguished from itby the presence of at least large aggre-gates of large atypical cells in areas andstrong CD30 expression.

Fig. 4.50 Plasmacytoma of the tongue. The plasmacytoma is accompanied by blood lakes.

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203Haematolymphoid tumours


Patients with NHL of the oral cavity andoropharynx are treated by radiotherapy,chemotherapy or a combination of thetwo. Some studies have shown that adju-vant chemotherapy is associated with abetter clinical outcome compared toradiotherapy alone {832,1009}. The five-year overall survival rate for localized dis-ease ranges from 50% to more than 80%{146,832,1009,1614,2505}. High clinicalstage, high histologic grade (large celllymphoma), and T-cell or NK/T cell phe-notype are poor prognostic indicators{146,1009,2250,2340,2809}.

Extramedullary plasmacytoma

ICD-O code 9734/3Extramedullary plasmacytoma can occurin the oral cavity and oropharynx, seeChapter 1 for details.

Langerhans cell histiocytosis

ICD-O code 9751/1

Oral involvement occurs in 10% ofpatients with Langerhans cell histiocyto-sis (LCH). 78% of these patients haveeosinophilic granulomas clinically, whilethe rest have multifocal multisystem dis-ease {1021}. Common oral symptomsinclude swelling, pain, gingivitis, looseteeth and ulceration. The majority ofpatients with intraoral lesions haveintraosseous lesions in the jaw bone,more commonly in the mandible. Theintraoral soft tissues may be secondarilyaffected, especially the gingiva, but thepalate, floor of mouth, buccal mucosaand tonsil can also be involved {1021,2043}. In a minority of patients with intra-oral soft tissue involvement, there is no

associated bony lesion {241,460,1731}.See chapter 7 for details.

Hodgkin lymphoma

Hodgkin lymphoma (HL) is predominant-ly a nodal-based disease, and primaryextranodal presentation is very rare.When it presents in extranodal tissues,the Waldeyer ring, particularly the pala-tine tonsil, is a common site {1274,1756}.Most patients present with localized dis-ease (stage I/II), with symptoms of chron-ic tonsillitis or tonsillar enlargement, withor without enlarged cervical lymphnodes. Other reported sites include theoropharynx {44,1756}, alveolar crest ofmandible {1659}, and maxillary gingiva{2554}. Most cases represent classical HL, asdetailed in the WHO Classification ofTumours of Hae ma to poietic andLymphoid Tissues {1197}, frequently ofmixed cellularity subtype and showingstrong association with Epstein-Barr virus(EBV) {1274}, although nodular lympho-cyte predominant HL may also rarelypresent in the Waldeyer ring (palatineand lingual tonsils) {391,1274}.

Extramedullary myeloidsarcoma

ICD-O code 9930/3

Gingival infiltrates occur in 3.5% ofpatients with acute myeloid leukaemia,predominantly in the monocytic ormyelomonocytic subtypes {622}.Clinically, there is diffuse enlargement ofthe interdental papillae, marginal gingivaand attached gingiva. The swollen gingi-va has a spongy to firm consistency,bright red to purple in colour. There is nocorrelation between gingival leukaemicinfiltrate and oral hygiene or peripheralwhite blood cell count {622}. Rare cases of extramedullary myeloidsarcoma may present as an isolatedtumour-forming intraoral mass. The mostfrequently involved sites are the palateand gingiva {52,761,2189,2614,2618}.While the tumour most often developswhile the patient has active disease, itmay precede the development of acutemyeloid leukaemia, or arise as blastictransformation of an underlying chronicmyeloproliferative disease or myelodys-

Fig. 4.51 Langerhans cell histiocytosis involving gingiva. The infiltrate comprises ovoid Langerhans cellswith deeply grooved nuclei, thin nuclear membranes and abundant eosinophilic cytoplasm. There are typi-cally many admixed eosinophils.

Fig. 4.52 Extramedullary myeloid sarcoma of the gingiva as the first sign of relapse of acute myeloidleukaemia. Beneath an intact stratified squamous epithelium, there is a diffuse and dense infiltrate of prim-itive myeloid cells.

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204

plastic syndrome. Histologically, there isa dense infiltrate of immature myeloidcells in the subepithelial soft tissue of thegingiva. Please refer to the section of‘Other uncommon haematolymphoidtumours’ in ‘Tumours of the nasal cavityand paranasal sinuses’ for further detailson extramedullary myeloid sarcoma.

Follicular dendritic cell sarcoma / tumour

Definition

Follicular dendritic cell (FDC)sarcoma/tumour is a rare neoplasmshowing morphologic and phenotypicfeatures of FDC.

ICD-O code 9758/3

Epidemiology, localization and clinical

features

It is an uncommon tumour of adulthood,and can affect patients over a wide agerange {368,2010,2043}. It can arise innodal and extranodal tissues, and theoral cavity is among the more commonlyinvolved extranodal sites {67,368,375,2010,2043,2249}. The patients usuallypresent with a painless mass involvingthe tonsil, palate or oropharynx.

Etiology

Occasional FDC sarcomas/tumoursappear to evolve from an underlying hya-line-vascular Castleman disease; the twolesions can present simultaneously or thelatter can precede the appearance of theformer by several years {359,368,374}.Overgrowth of FDC in the interfollicular

zone or ‘dysplasia’ of FDC may representthe precursor lesion.

Histopathology

Histologically, the tumour usually growsbeneath an intact stratified squamousepithelium. It usually exhibits pushingborders and comprises fascicles, whorls,nodules, storiform arrays or diffusesheets of spindly to ovoid tumour cellssprinkled with small lymphocytes. Thetumour cells usually show ill-defined cellborders, distinct nucleoli, and sometimesnuclear pseudoinclusions. There is a ten-dency for some nuclei to be haphazardlyclustered, and scattered multincleatedtumour cells are common. While nuclearpleomorphism is usually mild, some

cases can show significant nuclear atyp-ia and pleomorphism. The cytoplasm iseosinophilic, and often exhibits a fibrillaryquality as a result of the presence of inter-digitating cell processes. Very rarely, thetumour cells have distinct cell borders,and are polygonal or oval in shape. Themitotic count ranges from low to high,and some cases can show coagulativenecrosis. Occasional cases may showirregular interspersed cystic spaces.Besides being intermingled among thetumour cells, the lymphocytes can showcuffing around the blood vessels.The diagnosis has to be confirmed bydemonstration of FDC markers (e.g.CD21, CD23 and CD35), although thestaining can be patchy. Typically a mesh-

Tumours of the oral cavity and oropharynx

Fig. 4.54 Follicular dendritic cell sarcoma / tumour of oral cavity and oropharynx. A This palatal tumourinvades in pushing fronts. The main tumour is seen in the right. Smooth-contoured nodules (upper field)invade the adjacent normal structures. B Uncommon nodular growth pattern, recapitulating the ability offollicular dendritic cells to form follicles. C Typical storiform pattern, accompanied by a sprinkling of lym-phocytes. D This tumour consists of spindle cells with elongated nuclei, fine chromatin and small distinctnucleoli. Some cells have ill-defined cell borders, while others exhibit well-defined borders. E The tumourcell nuclei often appear haphazardly distributed, with some focal clustering. A few multinucleated tumourcells are also evident. The cytoplasm exhibits a fibrillary quality. F This example, composed of plump ovoidcells, shows a moderate degree of nuclear atypia and pleomorphism. Nucleoli are prominent.

FE

DC

A B

Fig. 4.53 Extramedullary myeloid sarcoma of thegingiva as the first sign of relapse of acute myeloidleukaemia. In areas, there is typically an Indian-filepattern of infitration.

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205

work pattern is highlighted. Cytokeratin isnegative. A proportion of cases expressepithelial membrane antigen or muscle-specific actin. Occasional cases canweakly express the pan-B marker CD20{2043}. Ultrastructurally, the tumour cellspossess interdigitating long slender cyto-plasmic processes and intercellulardesmosome junctions. Differential diag-noses include soft tissue sarcoma, poor-ly differentiated carcinoma, meningioma,and malignant melanoma.


Most cases of FDC sarcomas/tumourshave been treated by surgery, with orwithout adjuvant chemotherapy and

radiotherapy, with variable success. FDCsarcomas/tumours are low to intermedi-ate grade malignant tumours, with anoverall local recurrence rate of at least40% and a metastatic rate of at least28% {368,2010,2043}. Since somepatients can develop late metastasis(such as after more than 20 years) {438},long-term follow up is essential. Poorprognostic factors include significantcytologic atypia, extensive coagulativenecrosis, high proliferative index andlarge tumour size {368,2010}.

Haematolymphoid tumours

Fig. 4.55 Follicular dendritic cell sarcoma/tumour of the oral cavity. The surface epithelium is intact. Thistumour shows partial involvement of the tonsil (left field).

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206 Tumours of the oral cavity and oropharynx oropharynx

Definition

Malignant melanoma is a malignant neo-plasm of melanocytes or of melanocyteprecursors. It is characterized by prolif-eration of atypical melanocytes at theepithelial-connective tissue interfaceassociated with upward migration intothe epithelium and by invasion of theunderlying connective tissues. Althoughusually seen in the skin, melanomas mayalso arise from melanocytes in mucosae.

ICD-O code 8720/3

Epidemiology

Mucosal melanomas of the head andneck comprise just over 1% of allmelanomas and of these about 50%arise in the oral cavity. Oral mucosalmelanomas are therefore rare, represent-ing about 0.5% of oral malignancies{1085} and less than 0.01% of all oralbiopsies {122}. The annual incidence inthe USA is about 0.02 per 100,000 {170},but the lesion may be more common inother parts of the world including Japanwhere the oral cavity has been reportedas the most common site for melanomas{2528}.They arise in adults with an average ageof about 55, but with a uniform age distri-bution from 20–80 years {122,617,1085,2080,2127}. Very rare cases have beenreported in children. In most large seriesthere is a male predominance in a ratio ofabout 3:1 {122,617,2080} and somereports show males and females arealmost equal {144,1843}.

Etiology

No etiological factors are known to beassociated with oral melanoma.

Localization

Eighty percent of oral melanomas ariseon the palate, maxillary alveolus or gingi-vae. Other sites include the mandibulargingivae, buccal mucosa, floor of mouthand tongue.

Clinical features

Oral melanomas are usually asymmetric

with irregular outlines. They may beblack, grey or purple to red, and rarelyamelanotic. Typical lesions are com-posed of multiple or widespread areas ofmacular pigmentation with areas ofnodular growth. Purely macular lesionsmay be seen but over 50% of lesionspresent as nodules or as a pigmentedepulis. Ulceration is seen in about onethird of cases and invasion of bone iscommon. Many reports document long-standing ‘melanosis’ before the onset ofnodular lesions, with a history of up to 10years. Oral lesions are usually advancedat presentation with up to 75% of patientshaving metastases to cervical lymph

nodes, and 50% with distant metastases,usually to lung or liver {144,617,1085}.

Macroscopy

Tumours are usually 1.5-4 cm in diameterwith a black, macular or nodular surface.The cut surface is often homogeneouslyblack or darkly pigmented.

Histopathology

Oral melanoma may have in-situ (radial)and invasive growth phases, but the his-tological classification is not analogousto cutaneous lesions. Mucosal lesionsare similar to acral lentiginous melanomaof the skin {2652}, with junctional activityand upward migration but Pagetoid inva-sion is unusual. Atypical melanocyticlesions may progress to malignantmelanoma but there is little evidence forprogression of oral benign melanocyticnaevi to invasive malignancy {1085,2652}. Oral mucosal melanoma is, there-fore, classified as in-situ oral mucosalmelanoma, invasive oral mucosalmelanoma, and mixed in-situ and inva-sive lesions. Borderline lesions may betermed atypical melanocytic prolifera-tions {122,1085,2652}.Most lesions at presentation are invasiveor have mixed invasive and in-situ com-

Mucosal malignant melanoma P.M. Speight

Fig. 4.56 Malignant melanoma. multiple or wide-spread areas of dark macular pigmentation affect-ing the palate. Irregular nodular areas are alsoseen.

BAFig. 4.57 A in-situ growth phase showing atypical and enlarged melanocytes at the epithelial-connectivetissue interface. Melanocytes may show upward migration into the epithelium. B Invasive lesions showingconsiderable junctional activity, with atypical melanocytes invading into the underlying connective tissues.

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207Malignant melanoma

ponents. Less than 20% are solely in-situlesions. Typically, an oral melanoma iscomposed of sheets or islands of epithe-lioid melanocytes, which may bearranged in an organoid, or alveolar pat-tern. The cells have pale cytoplasm andlarge open nuclei with prominent nucleoliand occasionally they may be plasmacy-toid. Sheets and fascicles of spindle cellsmay also be seen, but are usually a minorpart of the lesion. Occasional lesionsmay be predominantly or wholly spin-dled. Over 90% of lesions containmelanin pigment that can easily bedemonstrated with stains such asMasson-Fontana or Schmorl’s. When present, the in-situ componentshows atypical naevoid cells arrangedsingly or in nests at the epithelial-con-nective tissue interface. Upward migra-tion of the cells is common, but Pagetoidislands, similar to those of superficialspreading cutaneous melanomas, arenot frequent. Invasion may be difficult todetermine but the presence of obviouslymalignant cells in the lamina propria indi-cates invasion and islands of cells largerthan those seen within the epitheliumsuggest an invasive growth phase. Mitoses are surprisingly sparse but areseen more frequently in invasive lesions.The overlying epithelium is usuallyatrophic and just over half of lesions areulcerated.

ImmunoprofileOver 95% of lesions are S100 positiveand negative for cytokeratins {144}.Although sensitive, S100 is not specific.More specific markers include HMB45,Melan-A or anti-tyrosinase, which stainabout 75% of lesions {2079}.

Genetics

Cutaneous melanomas may be associat-ed with familial melanoma syndromes,and melanoma-prone kindreds show fre-quent loss of heterozygosity or mutationsat several sites. Two tumour suppressorgenes, CDKN2A (at 9p21, which codesfor P16INK4A) and PTEN (at 10q23), and the oncogene CDK4 have beenidentified as important melanoma

susceptibility genes {269,1252,2713}.However, associations with these geneshave not yet been shown for oralmelanomas, and expression of varioustumour suppressor genes or oncogenesis variable and heterogeneous{1085,2555}.


The prognosis for oral melanoma is poorwith an overall median survival of about 2years and 5-year survival of less than20% {122,170,1085}. Stage is a predictorof survival but even localized tumours(stage I) show a 5-year survival of lessthan 50%. Depth of invasion (Breslow

thickness and Clark’s levels) is of limitedvalue in oral lesions. This is due to lack ofadequate studies and the fact that mostoral melanomas are deeper than 4 mm atpresentation {1085,1843,2080}.Nevertheless, lesions thicker than 5 mmmay have a significantly worse progno-sis. Other factors associated with poorprognosis include, vascular invasion,necrosis, a polymorphous tumour cellpopulation, and increasing age{170,1085,1843,2080}.

DCFig. 4.58 Malignant melanoma A Invasive lesions are typically composed of sheets of plump epithelioidmelanocytes. B Spindle cell areas are often seen. C HMB45 is one of the most specific markers formelanoma, but staining may be patchy. D S-100 antibodies are expressed strongly and uniformly in almostall lesions.

BA

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Metastases to bone

Definition

Distant spread of malignant neoplasm tothe head and neck from other parts of thebody. This is almost exclusively via ahaematogenous route.

Epidemiology

The most common malignant neoplasmswithin the jaws, apart from direct spreadfrom mucosal carcinomas, are metas-tases and the most frequent primary sitesare carcinomas of, in order of decreasingincidence, breast, kidney, lung, prostateand thyroid or colon {1098}. Maxillary andsinus metastases most frequently arisefrom renal carcinoma {202}.Metastasis accounts for approximately4% of all upper aerodigestive tract carci-noma {246}. The great majority of patientsare elderly, with mean age at diagnosis of55 years and the sex incidence variesfrom equal {2877} to a female preponder-ance accounted for by the prevalence ofbreast carcinoma. Asymptomaticmandibular metastases have been foundin 16% of carcinoma patients at autopsy{1025} but only approximately 1% of car-cinomas develop clinical metastasis tothe jaws during the course of the disease. Sarcomatous metastases are extremelyrare, usually Ewing sarcoma or osteosar-coma and arise in the second or thirddecade. Childhood malignant neoplasmsalso occasionally metastasise to the jaws.

Localization

The ratio of metastases in mandible tomaxilla is 5:1 or greater. Most mandibularmetastases develop in the angle of themandible below the inferior dental nervecanal, a minority affect the alveolus.

Clinical features

Common signs and symptoms includeloosening of teeth, swelling, failure to healof a dental extraction socket {1101},pathological fracture or nerve signs, par-ticularly paraesthesia and anaesthesia inthe mental region. Pain may be the onlyevidence of metastasis. After cortical per-foration, a soft tissue mass may be pres-ent. Some metastases are asymptomaticchance radiographic findings. The majority of jaw metastases are radi-olucent and poorly defined but occasion-al lesions are circumscribed. A minorityare osteosclerotic or mixed radiolucen-cies and these are usually breast orprostate carcinomas. Some show onlysubtle changes such as widening of theperiodontal ligament or may be invisibleon panoramic tomographic views andplain films. In such cases a bone scanmay reveal the metastasis. Radiographyhas low diagnostic yield for metastases{1025}.


Jaw metastases are the presenting signof malignancy in 20-30% of cases{1098,2877} but in most the primarylesion is known. Sometimes metastasisdevelops many years after treatment forthe primary lesion, particularly with renalcarcinoma. Metastatic spread to the jawsindicates UICC/AJCC Stage IV disease.

Histopathology

Histopathological appearances vary.Metastases are usually poorly-differenti-ated. If immunocyochemistry is requiredto aid clinical identification of sites of anoccult primary lesion, prostate specificantigen and thyroglobulin are the mostuseful stains.


Metastasis to the jaws usually indicateswidely disseminated disease and a poorprognosis with a 4-year survival of 10%{458}. Two thirds of patients die in lessthan 1 year {1101}. Depending on lesiontype and dissemination, radiotherapy orhormone therapy may be provided.Surgery may occasionally be of value inpalliative care.

Metastases to oral soft tissues

Metastasis to soft tissues is much morerare. It affects a similar age group, 40-70years old, and the commonest sites forprimary lesions in males are lung (onethird of cases) followed by kidney andskin. The commonest primary site infemales is breast {1100}. The commonestsite for metastasis is gingiva (55%)because of its fine capillary bed, followedby tongue (30%), though any site may beaffected. The predilection for gingiva ismostly lost after teeth are extracted{1100}. Lesions present as soft tissuemasses, often ulcerated, resembling trau-matic or reactive hyperplastic lesions.

Secondary tumours E.W. Odell

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bb9-chap4

Documents

van der waal

mucous retention phenomenon

acute myeloid leukaemia

t2 t3 t1

transplant lymphoproliferative disorder

granular cytoplasm set

rich lymphoplasmacytic infiltrate

n1 n2 n0