Today we will start anew chapter ,which is ORAL EPITHELIAL TUMORS ,MELANOCYTIC NAEVI AND MELANOMA , so we will talk

about oral epithelial tumors . Now we are going to start with HPV-associated lesions HUMAN PAPILLOMA VIRUS- ASSOCIATED LESIONS: ( HPV: Human papilloma virus) , *** HPV is a DNA virus with more than 75 types ,only few of these 75 types may cause oral lesions . ***HPV have several type around 16 are indentified in oral cavity *** HPV may be present in the normal epithelium, sometimes HPV may be found in the oral cavity without lesion ya3ni its not associated with lesions all the time. ***HPV is isolated from leukoplakia and SCC , but with a questionable role (the etiologic factors are not clearly known) .

***HPV associated lesions are :

1. squamous cell papilloma. 2. verruca valgaris ( common wart). 3. condyloma acuminatum (venereal wart ). 4. focal epithelial hyperplasia .
All of these lesions are elevated lesions.

FIRSTLY , Squamous cell papilloma:

one of the lesions that are caused by HPV is SQUAMOUS CELL PAPILLOMA : ** this lesion is considered as BENIGN SQUAMOUS EPTHELIAL TUMOR Benign :mean not reactive Benign squamous tumor not aglandular epithelial tumor it's epithelial tumor **Type of epithelial that lining the oral cavity :squamous epithelial so the HPV infect the squamous epithelium and induse lesion ** it may appear white(due to excessive keratin formation) or pink , but keep in your mind that most of papilloma are pinkish ** it occurs usually as a single lesion . ** its found mostly in the adults . ** the base maybe sessile or pedunculated ,but most of the time its pedunculated (has constricted neck)the base is narrower than the leasion . This is a white lesion it's mostly properly producing excessive amount keratin

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** it has multiple finger-like projections on the surface of mucosa supported by fibro vascular connective tissue cores underneath them , or it presents as cauliflower growth or as papillary projection ** this lesion may present on the dorsum of the tongue ,soft palate , ventral surface of the tongue or anywhere in the oral cavity . ( see the pictures below)

** in squamous cell papilloma the keratosis is variable ,the lesion may be hyperkeratotic or not <<while verruca vulgaris has hyperkeratosis most of the time as you will see below>>. ** the mitotic figures present but they are confined to the basal layer ( NO dysplasia) . IN THESE TWO PICTURES BELOW : IN : see the core of fibro vascular connective tissue(the arrow) , surfaced with thickened ,folded epithelium with occasional hyperkeratosis.

A Pic Fibrovascular core

IN B

: see the keratin on the surface (the arrow ).

SECONDLY , VERRUCA VULGARIS ( COMMON WART)

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its another disease caused by HPV , clinically its similar to squamous cell papilloma , so sometimes its hard to differentiate between them unless you take a biopsy and examine it microscopically . It's usually occurring on skin but it can occuar inside oral cavity , the viruses maybe transmitted by biting finger ** it may be sessile or pedunculated . ** its WHITEISH , most of the time it's produce excessive amount of keratin and when we look at the histopathology picture we see excessive amount of keratin, excessive layer and even stoking mean there is a liniment of keratin layer on the top of papillary surface or procase surface , there is a stoke of keratin, and if you look at epithelium you see prominent glandular layer , so a thick layer of keratin covers the surface of this lesion and its mostly orthokeratosis , with prominent granular cells layer most of the time.

Pic B This is a feature I look at when I diagnosis any specimen of verruca vulgaris Glandular cell layer (prominent) Koilocytes (which is a pyknotic cell with pyknotic nuclei and prevas (perinuclear vacuolization) Ilook to excessive amount of keratin Rete ridges if they inclined toward the center of lesion Then I said its a Verruca Vulgaris so if I don't see the inclination and excessive layer of keratin or granular cell layer Iwill go more to papilloma ** histopathologic features : (1) rete ridges at the edges of the lesion are inclined toward the center (this is a characteristic feature of verruca vulgaris) , see pic A below , (2) there are finger-like projections here but less than what we've seen in squamous cell papilloma .

A: inclined rete ridges

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**back to pic B, these cells( that the arrows pointing to) are called koilocytes ,
these are virally infected epithelial cell with HPV , since we have viral inclusion in these cells we will have cellular changes ( koilocytic changes) , one of these changes is the shrinkage of the nucleus so these cells will have pyknotic nuclei , another change is having vacuolization around the nuclei (perinuclear vacuolization ) , the third one is that these cells have crenated (irregular) borders . Again in these cells notice the pyknotic nuclei ,and the vacuoles around them ,remember they are called koilocytes. **in pic A we can see the broad base of the lesion so its sessile

** always keep in your mind that verruca vulgaris is hyperkeratotic most of the time.
THIRDLY , CONDYLOMA ACUMINATUM (VENEREAL WART):
Its another HPV-associated lesion ,it occurs mainly in the anogenital area but it may be seen intraorally. ** most of the time condyloma acuminatum has flat surface but sometimes we may see little roughness or cauliflower appearance a little bit on its surface. see pic A below ** it appears pink , ya3ni no excessive keratin production is seen. See pic A below

**the epithelium is hyperplastic , and as you saw all HPV associated lesions have
hyperplastic epithelium.

** it has blunted surface . ** its usually sessile and it reaches big sizes . ** it presents as multiple pink nodules and these nodules may fuse with each other and
form coalescence , giving us big elevated lesion.

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Multiple pink nodules

Histopathologic features :
*There are groves , it's exophytic lesion(on the surface) but doesnt show papillary like projection or even cauliflower appearance but it epithelial lesion *We see acanthosis , increase in thickness of epithelium and the width of rete ridges , so the epthilum grows , it go up the surface and down in the underlying tissue * It usually pinkish because it doesnt have exssive keratin , It's not like Verruca Vulgaris * koilocytes are seen here (arrows). HPV infected cell with pyknotic nuclei( prevaculization) , may show coalescence See the pics below

So Condyloma Acuminatum it has prominent acnthosis and elongation of rete rides ,they go down and go up on the surface ,broadening elongation and widening Viral infected cell (koilocyte) Kertenization not prominent feature

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FOURTHLY , FOCAL EPITHELIAL HYPERPLASIA (HECK'S DISEASE) :

** this lesion presents as multiple small papules on buccal mucosa , so usually the patient has several number of these nodules So it multiple, vacuoles and elevation on buccal mucosa If we take biopsy we will see mainaly Acanthosis Elongation and widening of rete ridges but also I will see koilocyte Question 1. Which on of the foue lesion is bengin tumor SCP 2. Which one is the common art Vv 3. Which one show very little kertaization relatively and acnthosis Ca 4. Which occur in multiple small Focal epithelial hyperplasia 5. Which one is commonly pedneculated with finger like projection Scp 6. Which one shows inclined rete ridges toward the center Vv 7. Which one shows koilocyte All of them because it's are virally infected cell

NOW , SQUAMOUS CELL CARCINOMA (SCC) :

EPIDEMIOLOGY : The epidemiology of SCC is easy and we talk about in leukoplakia because they show similarity as leukoplakia , may be predispose SCC Actually in body the malignant tumor that are presented by the premalignant tumor are not many , oral SCC is one of them it may predispose by leukoplakia Colonic adeno carcinoma it's pressed by adenoma Oral SCC is precede most of the time by leukoplakia so prevention of SCC is more important than advancement and than progression of treatment modarity because chemotherapy is getting advanced and also the radio therapy but the survival rate of patient not improve so it's very important to control the predisposing factor to diagnose scc early to improve prognosis of patient * SCC ; is a malignant tumor that originates from the squamous (flattened) cells of the epithelium.
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*SCC is the most common malignant tumor in the oral cavity ,it accounts for 90% of all oral malignancies. * SCC is consist 4% of all cancer in the USA&UK , and its up to 40% in India and southeast Asia because of the habits there (using tobacco , betel nut , betel quid and lime). * SCC is the 4th commonest cancer in men and 6th in women, and the 6th for both combined .
SCC used to be more common in males than in females , but nowadays the ratio is changing , and its getting more in females bcoz of the increase in smoking habit among females.

*SCC is the 8th in incidence in developed, but 3rd in developing countries.

It is more in developing countries than in the developed , even the Incidence in developed countries is on increase nowadays The age of onset usually 40 plus ,the age is decreasing or decling because young paient are smoking these days so they having more and more earlier scc

There is Geographic variations on the oral site of SCC like leukoplakia because it depend on different etiologic factor according to country , if we talking about
country with reverse smoking (the lesion will be on palate) If patient work outdoor most of the time in sun (lower lip) Area they use betel nut , betel quid and lime (on buccal sulcus where they hold

this preparation) Flower of mouth : high risk site site for leukoplakia Tobocoo by it self is a factor but also the number of cigarette and duration are important So the patient smoking 40 cigarette per day and more they are add 20 time increase risk of developing SCC comper with non smoker * the mortality (death rate) has not significantly changed despite advances in treatment, its about 30-40% in Western societies ( the mortality rate varies from area to another).

SCC Etiological Factors : 1) Tobacco *the most commonly associated factor with SCC is Tobacco , regardless how it's
used, smoked or non-smoked , if it's chewed ,topically used or placed in a sac in the oral cavity , alone or mixed with other ingradients. "there are smokeless types of tobacco that are chewed, or placed in the oral cavity " * in tobacco : the main carcinogenic material is nitrosamines that derived from nicotine ,in smoked tobacco beside nitrosamines the burning tobacco will produce polycyclic aromatic hydrocarbons that are carcinogenic ,too. These carcinogens
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will dissolve in saliva and reaches anywhere in the oral cavity especially the areas where saliva tends to pool( FOM, dorsal and ventral tongue, and soft palate). *In India , Malaysia, and other Asian countries tobacco is mixed with other materials( like ; betel nut ,lime , , areca or others) so the likelihood of having SCC will be more compared to normal people. (about 40 times as the dr said) *in India the habit of reverse smoking increases the risk of having palate cancer 40 times more than non smokers . <<depending on our textbook page 138, reverse smoking means holding the cigarette in the opposites way with the burning end inside the mouth>>. *the habit of using tobacco affects the location of the cancer , suppose the person uses tobacco by placing it in the buccal sulcus this location will be at high risk of having SCC. * Types of tobacco, methods and the location where its placed influence the relative risk Pipe and cigarmore likely to develop lip cancer. Reverse smokingpalate cancer ( because the carcinogens and the heat are directly on the palate) Regular smokersFloor of the mouth, tongue, soft palate .(I think this point is important because the dr repeated it many times ). *Heavy smokers ( more than 40 cigarettes/day) are at 10-20 times increased risk , even if he stops smoking he needs 10 years to go back to the normal risk. * Betel Quid (pan) is a mixture of betel nut, lime and tobacco , placed and rapped in the betel leaf ,then used either by smoking or topically , the interactions between these components may later on induce SCC at the sites where it's placed . At the beginning leukoplakia may appear if that happens we should do follow up if the lesion starts to show filiform surface or ulceration the person should worry about it because these are signs of scc.

As a summary:
.Betel nut and lime and tobacco in betel leaf they use In India:* , these alkaloids are carcinogenic). alkaloids(the betel nut releases Tobacco increase the risk when " baccothey use betel nut and lime but without to In Malysia:*placed in the pan " *Tobacco and alcohol are the most important factors ,and if they used together the effect will dramatically increase because alcohol will act as solvent to carcinogens (nitrosamine) so the potential of having SCC will increase (Synergistic effect) , especially if the person has atrophic epithelium due to lichen planus , iron deficiency ,submucous fibrosis or whatever. **Areca nut (differs than betel nut), it increases the risk of sub mucous fibrosis which is a premalignant ,epithelial atrophy condition ,,, betel Quid itself is a predisposing factor for SSC Slide 25

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This is details about Rabd in the leaf later on the alkaloids will be released from the nut when they chew it at the end these alkaloids are carcinogenic in addition to nitrous amine ,,,In Malaysia they use it but without tobacco . Slide 26 2)AlCOHOL is having direct effect by dissolving the carcinogenic material it is dose & time related & it also affect the liver so the PTs may have iron deficiency, folic acid deficiency, vitamins deficiency, mal absorption as indirect effect all of this will affect the oral mucosa it will be thin and more permeable to toxic material because squamous epithelium is a barrier so we dont want it to be thin but it may get thin in nutritional deficiency. Slide 27 Mechanism of alcohol: -enhance the transport of carcinogenic -solvent of carcinogenic material -mucosal atrophy so it may suppress the immune system and if the immunity is lowered the potential for malignancy is increased ((like the AIDS pts they have highy % of malignancy )) Slide 28 Mouth wash is containing alcohol its questionable if they have carcinogenic ro if they have harm full effect. Slide 29 3) Diet and nutrition The effect of iron deficiency on the mucosa >> it becomes atrophic >> more permeable to carcinogens In some disease like sideropenic anemia or plumme-vinson syndrome they have iron deficiency and they are in increased risk in esophageal, pharyngeal and oral cancer and other lesion like lichen planus >(epi is atrophic so its more permeable to carcinogen ) so its MAYBE a predisposing factor for SSC Slide 30

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Vit A is important for maintenance of the epithelium, some will use retinol or retin A to treat acne or certain skin lesions , vit A is important for differentiation & maturation of the epithelium if there is vit A deficiency then the oral epithelium is atrophic *vit A,C,E are anti oxidants & its against aging & its important to counter act the sun damage to skin these vitamins are important to prevent oral SCC Slide 31 4) Dental factor We mention something about chromatic keratosis when we have sharp cusp or fractured tooth , sharp filling that causes low grade continuous trauma we dont like to have this situation ( low grade trauma will give white lesions acute or high grade trauma will give ulcers ) *so we dont keep a source of chronic trauma in pts mouth bcz there is a questionable concern about this as an etiologic factor for SSC * studies found that SCC patients are with Poor oral hygiene or faulty restorations, sharp edges of teeth, or illfitting dentures , but they also found that those patients are heavy smokers and drinkers , so its not really established if poor oral hygiene or sharp edges . Are really associated factors with SCC or not.

**Chronic Mechanical irritation can act as a cancer promoter, but not initiator (because of oxidants release as mentioned). Which one come first initiation or promotion?? Initiation We need carcinogenic material or mutation to a certain cell cycle gene as initiation & then the chronic trauma may be the promoter to develop the cancer Slide 32 5) occupational risks
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Outdoor occupation may increase of the lip cancer , pts working outdoors under the sun for long durations especially if they are fair skinned , some times the lip cancer may be preceded by a premalignant condition called solar keratosis like the leukoplakia on the lip Slide 33 6)viruses HSV, human papiloma virus HPV, EBV are not confirmed that they have etiologic role Slide 34 & 35 EPV it has arole in nasopharyngeal carcinoma it is confirmed HPV it is important in the uterine cervix carcinoma ,, in the oral carcinoma it was isolated from certain SSC lesions but it eas also isolated from healthy pts so its role is not confirmed Bet the HPV the theory behind HPV involvement is that the HPV may insert its genetic material in locations close to P53 & retenoplastoma gene RP gene so it may ulter its function & from here it may predispose for SSC *HPV based in these roles & based on the fact that it is associated with uterine cervix carcinoma it may have arole in the oral SSC *Which virus may ulter the P53 & RP gene? HPV Slide 36 -immunosuppression in the AIDS pts they have a high incidence of oral carcinomas and other oral tumors , in some pts having transplant like kidney transplant bcz they take immunosuppressor so that they prevent rejection they may gen increase of oral SSC especially the lip cancer - we said that smoking , alcohol , iron deficiency all will effect negatively the immune response and may increase the likely hood of getting SSC Slide 36 Microbial infections

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In leukoplakia there is candida and it infect the leukoplakia , we have 2 groups of researchers : -the fist said that the candida secondarily infect the leukoplakia - the second said that candida is induce leukoplakia We have a group of high risk leukoplakia called candidal leukoplakia which usualla nonhomogenous & carries higher risk to transform to SSC # Why the candida is important in the etiology of SSC? We will talk about it in the infections CH. but mainly bcz candida produce a material which is very similar to nitrose amine that found in all kinds of tobacco

Slide 37 From chronic infections we have the syphilis which is bacterial infection it caused by tryponomia pllidium & tertiary syphilis we have atrophic glossitis which is not good bcz it is more permeable and also tertiary syphilis pts may have syphilitic leukoplakia and it may precede SSC but late stage of syphilis is rare bcz of treatment Slide 39 etiological factors summery Slide 40 We have different genes controlling the cell cycle but they are mainly divided in to : 1) Protooncogenes : stimulate the division 2) Tumor suppressor genes : stop the cell cycle Oral cancer like other cancer it is multi step process it needs several mutations and these mutations ma affect the proto-oncogene and the tumor suppressor gene until they drive the cell into uncontrolled cellular division Slide 42 very important Model for genetic progression This model for loss of heterozygocity (( is a loss of genetic material from specific locations at ch9P petet arm ,short arm))
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Model for genetic progression based on loss of heterozygosity (LOH): (loss of genetic material from specific locations on chromosomes) 1. normal mu

dysplasia; so p53 loss occur in the early stages of Dysplasia(of tumor development). Dysplasia may stay as its forever, regress or progress. 3. dysplasia:-

We will have predysplastic lesion experimental in the lab & from studies but until now we have only predysplastic lesions If we take a lesion with epithelial dysplasia but it is having additional loss of heterozygocity at other locations then this may develop into carcinoma in site 2 ( having sever dysplasia involving the full thickness of the epithelium you cannot recognize the keratin from the basal layer) Why in site 2? Bcz there is no invasion yet when there is invasion then it is SSC & this case is still waiting for more loss of heterozygocity to develop the invasion so we have several steps we can do our intervention at any step if you identify the dysplastic lesion you can ask the pt to stop smoking to follow up the lesion or even to remove it if it is small bcz its already ultered Slide 43 Mutation to tumor suppressor gene will enhance cell cycle bcz you stop the stop of the cycle

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Proto-onco gene once it is mutated it will be oncogene & this is not normal its indicate un controlled cell cycle so there will be deregulation of the cell proliferation & tumor formation Slide 44 e.g of oncogen c-myc,ras and erbB-1 slide 45 *P53 stop the cell cycle in G1 phase , it has 2 check points , it is the guardian of the genome * most of the body tumors have a mutation in the P53 gene

The END Forgive us for any mistakes Done by : Hiba Abu-jumah & Razan AL- Shweki :D

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