Oral cancer pwr.pnt

Comprehensive review of Comprehensive review of malignancies of Lips and Oral malignancies of Lips and Oral

CavityCavity

DR Kamlesh K. DubeyDR Kamlesh K. Dubey

Deptt. Of Deptt. Of OtorhinolaryngologyOtorhinolaryngology

AIIMS, New DelhiAIIMS, New Delhi

Cellular system of Oral Cellular system of Oral CavityCavity

Human squamous cell epithelium: Human squamous cell epithelium: important role as barrier against- important role as barrier against- mechanical, physical, pathological injury.mechanical, physical, pathological injury.

Limited availability of well defined Limited availability of well defined culture system for studying oral culture system for studying oral epithelial cell biology.epithelial cell biology.

Various molecular markers: for early Various molecular markers: for early diagnosisdiagnosis

EPIDEMIOLOGYEPIDEMIOLOGY

Oral cavity: extends from vermillion border Oral cavity: extends from vermillion border of lips to plane between junction of hard of lips to plane between junction of hard palate and soft palate.palate and soft palate.

Include : oral cavity- buccal mucosa, tongue, Include : oral cavity- buccal mucosa, tongue, gingiva, retromolar trigon, floor of mouth, gingiva, retromolar trigon, floor of mouth, hard palatehard palate

High incidence in India, France, SE asia.High incidence in India, France, SE asia. 40% of HN cancer40% of HN cancer Age of onset 6-7Age of onset 6-7thth decade, sex ratio 3:1 decade, sex ratio 3:1

Pre-Malignant LesionsPre-Malignant Lesions

LeukoplakiaLeukoplakia - chronic, white, verrucous plaque - chronic, white, verrucous plaque with histologic atypiawith histologic atypia Severity linked to the duration and quantity of tobacco Severity linked to the duration and quantity of tobacco

and alcohol useand alcohol use Occur anywhere in the oral cavity Occur anywhere in the oral cavity Lip, tongue, or floor of the mouth lesions are prone for Lip, tongue, or floor of the mouth lesions are prone for

progression to SCCprogression to SCC ErythroplakiaErythroplakia - non-inflammatory erythematous - non-inflammatory erythematous

plaque plaque Analagous to intra-oral erythroplasia of Queyrat or SCC Analagous to intra-oral erythroplasia of Queyrat or SCC

in situin situ Biopsies - severe dysplasia and areas of frank invasionBiopsies - severe dysplasia and areas of frank invasion

LeukoplakiaLeukoplakia

ErythroplakiaErythroplakia

Pre-Malignant Lesions…Pre-Malignant Lesions…

Submucous fibrosis Submucous fibrosis generalized white discoloration of oral mucosa generalized white discoloration of oral mucosa

with progressive fibrosis, painful mucosal with progressive fibrosis, painful mucosal atrophy and restrictive fibrotic bands atrophy and restrictive fibrotic bands

individuals who chew betel quid, a concoction individuals who chew betel quid, a concoction of tobacco, lime, areca nut and betel leavesof tobacco, lime, areca nut and betel leaves

Ultimately leads to trismus, dysphagia and Ultimately leads to trismus, dysphagia and severe xerostomiasevere xerostomia

5 - 10 % progress to SCC5 - 10 % progress to SCC

Cancerous lesion of Lips& Cancerous lesion of Lips& Oral cavityOral cavity

Lips –SCC, Melanoma, BCC(rare)Lips –SCC, Melanoma, BCC(rare) Oral cavity:Oral cavity:

-- scc: 9/10 incidence-- scc: 9/10 incidence

--verrucous ca: <5% low grade, --verrucous ca: <5% low grade, slow growing rarely metastasizes slow growing rarely metastasizes with tendency to invade deep tissue.with tendency to invade deep tissue.

Cancerous lesion of Lips& Cancerous lesion of Lips& Oral cavityOral cavity

Minor salivary gland tumor: Minor salivary gland tumor:

-in the glands lining the oral cavity-in the glands lining the oral cavity

-adenoidcystic ca, mucoepidermoid ca,-adenoidcystic ca, mucoepidermoid ca,

adenocarcinoma.adenocarcinoma.

-Sarcoma-Sarcoma

IncidenceIncidence

Globally >300,000 people diagnosed/yearGlobally >300,000 people diagnosed/year Eighth most common malignancyEighth most common malignancy India –upto 40% of all malignanciesIndia –upto 40% of all malignancies M>FM>F Raising trendRaising trend 6-76-7thth decade decade Most of the people are dying because of Most of the people are dying because of

ignoranceignorance

INCIDENCEINCIDENCE

Demographic and clinical profile of oral Demographic and clinical profile of oral squamous cell carcinoma patients: a squamous cell carcinoma patients: a retrospective study ( Shenoi R, Sharma BK, retrospective study ( Shenoi R, Sharma BK, et.al, Indian J Cancer. 2012 Jan;49(1):21-6:et.al, Indian J Cancer. 2012 Jan;49(1):21-6:

Most common site: mandibular alveolusMost common site: mandibular alveolus

Major cause: tobacco chewingMajor cause: tobacco chewing

Majority of patients presented in stage IIIMajority of patients presented in stage III

Majority presented within 6 months of onsetMajority presented within 6 months of onset

Risk FactorsRisk Factors

Tobacco:Tobacco: About 90% of people with oral About 90% of people with oral cavity and oropharyngeal cancer use tobacco cavity and oropharyngeal cancer use tobacco

Alcohol:Alcohol: Drinking alcohol strongly increases a Drinking alcohol strongly increases a smoker's risk of developing oral cavity and smoker's risk of developing oral cavity and oropharyngeal cancer. oropharyngeal cancer.

Ultraviolet light:Ultraviolet light: More than 30% of patients More than 30% of patients with cancers of the lip have outdoor with cancers of the lip have outdoor occupations associated with prolonged occupations associated with prolonged exposure to sunlight. exposure to sunlight.

Irritation:Irritation: Long-term irritation to the lining of Long-term irritation to the lining of the mouth caused by poorly fitting dentures the mouth caused by poorly fitting dentures

Risk Factors Cont…Risk Factors Cont…

Poor nutrition: Poor nutrition: A diet low in fruits and A diet low in fruits and vegetables is associated with an increased risk vegetables is associated with an increased risk

Mouthwash:Mouthwash: Some studies have suggested that Some studies have suggested that mouthwash with a high alcohol content mouthwash with a high alcohol content

Human papillomavirus (HPV) infection:Human papillomavirus (HPV) infection: Immune system suppressionImmune system suppression:: Age: Age: The likelihood of developing oral and The likelihood of developing oral and

oropharyngeal cancer increases with age, oropharyngeal cancer increases with age, especially after age 35. especially after age 35.

Gender:Gender: Oral and oropharyngeal cancer is twice Oral and oropharyngeal cancer is twice as common in men as in women as common in men as in women

How tobacco affectsHow tobacco affects

Tobacco smoke contains >4000 Tobacco smoke contains >4000 chemicals, at least chemicals, at least 60 shown to be 60 shown to be carcinogens.carcinogens.

Smoke less tobacco: Smoke less tobacco:

main form: chewing, snuffmain form: chewing, snuff

at least 28 carcinogens found in smokeless at least 28 carcinogens found in smokeless formform

HabitHabit NoneNone Betel nut ChewingBetel nut Chewing Smoking onlySmoking only Betel chewing + Betel chewing +

Tobacco chewingTobacco chewing Betel chewing + Betel chewing +

SmokingSmoking Betel+Tobacco+smokiBetel+Tobacco+smoki

ngng

1%1% 4%4% 3-6%3-6% 8-15%8-15%

4-25%4-25% 20%20%

Relative Risk factors for Oral Relative Risk factors for Oral CancersCancers

Relative Risk %Relative Risk %

How Alcohol affectsHow Alcohol affects

Chronic alcohol exposure results in increased Chronic alcohol exposure results in increased cancer incidence in animal model.cancer incidence in animal model.

Acetaldehyde , reactive oxygen species- main Acetaldehyde , reactive oxygen species- main mutagenmutagen

Acetaldehyde: directly binds to DNA, alters Acetaldehyde: directly binds to DNA, alters methyl transfer leading to hypomethylation methyl transfer leading to hypomethylation leading to alerted gene productsleading to alerted gene products

Alcohol promotes cytochrome P450- which Alcohol promotes cytochrome P450- which increases activation of increases activation of procarcinogens( tobacco, alcohol).procarcinogens( tobacco, alcohol).

Alcohol can act as solvent facilitating entry of Alcohol can act as solvent facilitating entry of carcinogens into cellscarcinogens into cells

Recent study on role of Recent study on role of alcoholalcohol

Joint effects of alcohol consumption and polymorphisms in alcohol and oxidative stress metabolism genes on risk of head and neck cancer (Hakenwerth AM, et.al. cancer epidemiology biomarkers prev 2011 Nov;20(11):2438-49. Epub 2011 Sep 22)

Concluded that alterations in alcohol and oxidative stress pathways influence SCCHN carcinogenesis and warrant further investtigation

Role of HPV in Oral SCCRole of HPV in Oral SCC

Role of human papilloma virus in the oral carcinogenesis: an Indian perspective (Chocolatewala NM, et.al. J Cancer R Ther. 2009 Apr-Jun;5(2):7-17).

Association strongest for Oropharynx, specially cancer of tonsils followed by base of tongue.

High risk HPV-16 predominate type. Commonly affects younger age groups , male, non

smokers. Better outcomes, more responsive to RT, higher

survival rate.

INHERITED RISK FACTORSINHERITED RISK FACTORS

A review of inherited cancer syndromes and their A review of inherited cancer syndromes and their relevance to oral squamous cell carcinoma (Prime SS, relevance to oral squamous cell carcinoma (Prime SS, Thakker NS, et.al. Oral oncology 2001 Jan;37(1):1-16: Thakker NS, et.al. Oral oncology 2001 Jan;37(1):1-16: examined genetic defects associated with inherited examined genetic defects associated with inherited cancer syndromes and their relevance to oral cancer.cancer syndromes and their relevance to oral cancer.

Defective DNA repair mechanism: xeroderma Defective DNA repair mechanism: xeroderma pigmentosa, ataxia telangiectasia, bloom syndrome, pigmentosa, ataxia telangiectasia, bloom syndrome, fanconi syndromefanconi syndrome


Defective DNA repair mechanism: Defective DNA repair mechanism: xeroderma pigmentosa, ataxia xeroderma pigmentosa, ataxia telangiectasia, bloom syndrome, telangiectasia, bloom syndrome, fanconi syndromefanconi syndrome

Tumor suppressor gene(p53) defect: Tumor suppressor gene(p53) defect: Li Fraumeni syndrome.Li Fraumeni syndrome.


Relationship between ABO blood Relationship between ABO blood groups and oral cancer (Jaleel BF, et. groups and oral cancer (Jaleel BF, et. al. Indian J Dental Research 2012 al. Indian J Dental Research 2012 Jan;23(1):7-10:Jan;23(1):7-10:

found that people with blood group A found that people with blood group A had 1.46 times higher risk of had 1.46 times higher risk of developing oral cancer as compared developing oral cancer as compared with other blood group.with other blood group.


Allergies and risk of head and neck cancer (Michaud DS, et.al. Cancer Causes Control. 2012 (Michaud DS, et.al. Cancer Causes Control. 2012 Aug;23(8):1317-22. Epub 2012 Jun 19).Aug;23(8):1317-22. Epub 2012 Jun 19).

Case control studyCase control study Allergies have heightened Th2 immunityAllergies have heightened Th2 immunity Had a 19% lower risk of HNSCC.Had a 19% lower risk of HNSCC. Statistically significant for oropharyngeal cancer.Statistically significant for oropharyngeal cancer. HPV status does not confound or modify HPV status does not confound or modify

associations with allergies.associations with allergies.

MOLECULAR BIOLOGYMOLECULAR BIOLOGY

Cytogenetic : chromosomes Cytogenetic : chromosomes 3,5,8,11,17,18.3,5,8,11,17,18.

Tumor suppressor genes inactivation: Tumor suppressor genes inactivation: p16,p21,p53,RB gene.p16,p21,p53,RB gene.

Proto-oncogene activation: Proto-oncogene activation: cyclinD1/PRADD1.cyclinD1/PRADD1.

Growth factors /receptors overexpression: Growth factors /receptors overexpression: EGF,EGF-R,TGF-ɑ,HER-2/neu,FGF,FGF-EGF,EGF-R,TGF-ɑ,HER-2/neu,FGF,FGF-R,PDGF).R,PDGF).

MOLECULAR BIOLOGYMOLECULAR BIOLOGY

RAS family oncogene.RAS family oncogene. Telomeres, telomerase, cell senescenceTelomeres, telomerase, cell senescence Tumor immunology(role of TIL, CTL, IL-Tumor immunology(role of TIL, CTL, IL-

2/4/6)2/4/6) Tumor invasion and metastasis:Tumor invasion and metastasis:

(endothelial (endothelial proliferation:PGE2,TGFproliferation:PGE2,TGFββ,FGF,VEGF),MMP,FGF,VEGF),MMP

MOLECULAR PROGRESSION MODEL OF HNSCC MOLECULAR PROGRESSION MODEL OF HNSCC CARCINOGENESISCARCINOGENESIS

Normal squamous mucosaNormal squamous mucosaEGF, EGFREGF, EGFROverexpressionOverexpression

Squamous hyperplasia Squamous hyperplasia Telomerase activation Telomerase activation p16 inactivationp16 inactivation

DysplasiaDysplasiaPRAD-1 amplification PRAD-1 amplification 3p deletion3p deletion

p53 inactivation p53 inactivation Carcinoma in-situCarcinoma in-situ4q, 5q, 8p, 13q4q, 5q, 8p, 13qdeletiondeletion Invasive carcinomaInvasive carcinoma

Matrix metalloproteinaseMatrix metalloproteinaseOver-expression Over-expression

MetastasisMetastasis

DNA changesDNA changes

P53, p16, Ki67 immunoexpression in oral scc ( Dragomir LP, et.al, Rom jo morph embry 2012; 53(1)89-93:

positivity index- increased for p16 tumor invasion- identified with p53, Ki67.Study highlights value of immunostain for p16

in identifying dysplastic lesionPredictive importance of p53, Ki16 markers in

identifying aggressive form of tumour.

DNA CHANGESDNA CHANGES

Immunohistochemical p53, Ki16, Immunohistochemical p53, Ki16, hTERT in oral scc( Abraho AC hTERT in oral scc( Abraho AC et.al.Brazil oral research 2011 Jan-et.al.Brazil oral research 2011 Jan-Feb;25(1):34-41:Feb;25(1):34-41:

p53 positivity in 93.3% of PMD, p53 positivity in 93.3% of PMD, 43.3% of OSCC, 80% OEH.43.3% of OSCC, 80% OEH.

Site of oral cavity Site of oral cavity

Tongue : 35%Tongue : 35% Floor of mouth: 30%Floor of mouth: 30% Lower alveolus: 15%Lower alveolus: 15% Buccal mucosa: 10%Buccal mucosa: 10% Upper alveolus/hard palate: 8%Upper alveolus/hard palate: 8% RMT: 2%RMT: 2% Lips: lower-93%, upper-5%, commissure- Lips: lower-93%, upper-5%, commissure-

2%2%

SymptomsSymptoms

a sore in the mouth that does not heal a sore in the mouth that does not heal (most common symptom) (most common symptom)

pain in the mouth that doesn't go away pain in the mouth that doesn't go away (also very common) (also very common)

a persistent lump or thickening in the a persistent lump or thickening in the cheek cheek

a persistent white or red patch on the a persistent white or red patch on the gums, tongue, tonsil, or lining of the mouth gums, tongue, tonsil, or lining of the mouth

a sore throat or a feeling that something is a sore throat or a feeling that something is caught in the throat that doesn't go away caught in the throat that doesn't go away

Increased salivationIncreased salivation

More SymptomsMore Symptoms

difficulty chewing or swallowing difficulty chewing or swallowing difficulty moving the jaw or tongue difficulty moving the jaw or tongue swelling of the jaw that causes dentures to swelling of the jaw that causes dentures to

fit poorly or become uncomfortable fit poorly or become uncomfortable loosening of the teeth or pain around the loosening of the teeth or pain around the

teeth or jaw teeth or jaw voice changes voice changes a lump or mass in the neck a lump or mass in the neck weight loss weight loss persistent bad breath persistent bad breath

Patient WorkupPatient Workup

History History Clinical examinationClinical examination InvestigationsInvestigations


Investigations :Investigations :

Primary: photographsPrimary: photographs

incisional biopsy incisional biopsy

FNACFNAC

OrthopantogramOrthopantogram

CXRCXR

ECGECG

Routin blood investigationsRoutin blood investigations


Investigations: for stagingInvestigations: for staging

- CT face + neck ± CT chest- CT face + neck ± CT chest

- MRI- MRI

- USG of neck or primary ± USG guided - USG of neck or primary ± USG guided

FNAC of suspicious lymphadenopathyFNAC of suspicious lymphadenopathy

- PET- PET

INVESTIGATIONS FOR INVESTIGATIONS FOR RECONSTRUCTIONRECONSTRUCTION

Allen’s test of vascular supply to hand if a radial Allen’s test of vascular supply to hand if a radial forearm flap anticipated.forearm flap anticipated.

MRA of leg vessels if composite fibula MRA of leg vessels if composite fibula reconstruction anticipated.reconstruction anticipated.

Colour Doppler of chest , abdomen if DCIA(deep Colour Doppler of chest , abdomen if DCIA(deep circumflex iliac artery) free flap anticipatedcircumflex iliac artery) free flap anticipated

CAD/CAM models if complex composite CAD/CAM models if complex composite reconstructionreconstruction

Dental impression for all maxillary tumoursDental impression for all maxillary tumours

STAGING OF THE DISEASESTAGING OF THE DISEASE

American joint committee on cancer:American joint committee on cancer:

T , N , MT , N , M

Tx- primary tumour cannot be assessedTx- primary tumour cannot be assessed

T0- No evidence of primary tumourT0- No evidence of primary tumour

T1- ≤ 2cm in greatest dimensionT1- ≤ 2cm in greatest dimension

T2- 4cm < 2cm> in greatest dimensionT2- 4cm < 2cm> in greatest dimension

T3- > 4cm in greatest dimensionT3- > 4cm in greatest dimension


T4a- Oral cavity: tumour invades through T4a- Oral cavity: tumour invades through cortical bone, into deep(extrinsic) muscle of cortical bone, into deep(extrinsic) muscle of tongue, maxillary sinus or skin.tongue, maxillary sinus or skin.

Lips: cortical bone, inferior alveolar Lips: cortical bone, inferior alveolar nerve, floor of mouth, skin i.e. chin or nose.nerve, floor of mouth, skin i.e. chin or nose.

T4b- involves masticator space, pterygoid T4b- involves masticator space, pterygoid plates, skull base and/or encases internal plates, skull base and/or encases internal carotid arterycarotid artery


N stage:N stage:

Nx- regional lymph nodes can not be Nx- regional lymph nodes can not be assessed.assessed.

N0- no regional lymph node metastasis.N0- no regional lymph node metastasis.

N1- metastasis in a single ipsilateral N1- metastasis in a single ipsilateral lymph node ≤ 3cm in greatest dimension.lymph node ≤ 3cm in greatest dimension.

N2a- metastasis in a single ipsilateral LN N2a- metastasis in a single ipsilateral LN > 3cm but < 6cm in greatest dimension.> 3cm but < 6cm in greatest dimension.


N2b- metastasis in multiple ipsilateral LNs, N2b- metastasis in multiple ipsilateral LNs, none > 6cm in greatest dimension.none > 6cm in greatest dimension.

N2c- metastasis in B/L or C/L LNs, none > 6 N2c- metastasis in B/L or C/L LNs, none > 6 cm.cm.

N3- metastasis in a LN > 6 cm in greatest N3- metastasis in a LN > 6 cm in greatest dimensiondimension

M stage: Mx- cannot be assessed, M0- no M stage: Mx- cannot be assessed, M0- no distant metastasis, M1- distant metastasisi.distant metastasis, M1- distant metastasisi.

Stage Grouping Stage Grouping

Stage 0Stage 0 TisTis N0N0 M0 M0

Stage IStage I T1T1 N0N0 M0M0

Stage IIStage II T2T2 N0N0 M0M0

Stage IIIStage III T1, T2T1, T2 N1N1 M0M0

T3T3 N0, N1N0, N1 M0M0

Stage IV A Stage IV A T1, T2, T3T1, T2, T3 N2N2 M0M0

T4aT4a N0, N1, N2N0, N1, N2 M0M0

Stage IV BStage IV B Any TAny T N3N3 M0M0

T4b T4b Any NAny N M0M0

Stage IV CStage IV C Any TAny T Any NAny N M1M1

TREATMENTTREATMENT

Treatment goals: to eradicate primary Treatment goals: to eradicate primary tumor and LN metastasis, to maintain tumor and LN metastasis, to maintain function, cosmetic reconstructionfunction, cosmetic reconstruction

Factors affecting choice of treatment:Factors affecting choice of treatment:

tumor factortumor factor

patient factorpatient factor

resource factorresource factor

Treatment Goals forTreatment Goals forCancer of the Oral CavityCancer of the Oral Cavity • • Cure of cancerCure of cancer • • Preservation or restoration of Preservation or restoration of

form and functionform and function • • Avoid or minimize sequelae of Avoid or minimize sequelae of

treatmenttreatment • • Prevent second primary Prevent second primary

cancerscancers

TUMOR FACTORS AFFECTING TUMOR FACTORS AFFECTING TREATMENTTREATMENT

• • SiteSite • • Size (T stage)Size (T stage) • • LocationLocation • • MultiplicityMultiplicity • • Proximity to boneProximity to bone • • Pathological featuresPathological features • • Histology, grade, depth of invasion, tumorHistology, grade, depth of invasion, tumor typetype • • Status of cervical lymph nodesStatus of cervical lymph nodes • • Previous treatmentPrevious treatment

TREATMENTTREATMENT

Patient factors:Patient factors:

age, general medical condition,age, general medical condition,

performance status, occupation, performance status, occupation,

lifestyle(smoking/drinking)lifestyle(smoking/drinking)

socioeconomic considerationssocioeconomic considerations

previous treatmentprevious treatment

TREATMENTTREATMENT

Physician factors:Physician factors:

surgery, radiotherapy, chemotherapysurgery, radiotherapy, chemotherapy

nursing & rehabilitation services,nursing & rehabilitation services,

dental, prosthetics, support servicesdental, prosthetics, support services

Treatment Treatment

Surgery Surgery Radiotherapy Radiotherapy Chemotherapy Chemotherapy ImmunotherapyImmunotherapy Targeted therapyTargeted therapy Gene therapyGene therapy

Treatment of ChoiceTreatment of Choice

Stage I , II: single modality treatment I , II: single modality treatment is effective and preferable.is effective and preferable.

Stage III , IV: multimodal therapy is Stage III , IV: multimodal therapy is essential essential

TREATMENTTREATMENT SURGERY:SURGERY:

Early stage T1/2No tumor: Wide excision +/ - NDEarly stage T1/2No tumor: Wide excision +/ - NDHigh risk of locoregional recurrent (40%)High risk of locoregional recurrent (40%)

Management of Management of No NeckNo Neck::High incidence of occult metastasis in the clinically High incidence of occult metastasis in the clinically

No No Neck (15-43%)Neck (15-43%)Controversy : Observation or Surgery/RadiationControversy : Observation or Surgery/RadiationDepend on primary site. Depend on primary site. Should be have minimal morbidityShould be have minimal morbidityELND if risk of occult meta >20%. (SND/SOHND).ELND if risk of occult meta >20%. (SND/SOHND).

Locally advanced tumor: Combined modality treatmentLocally advanced tumor: Combined modality treatment

Classification of NDClassification of ND

1991 Classification:1991 Classification: RNDRND Modified RNDModified RND Selective ND:Selective ND:

SupraomohyoidSupraomohyoidLateralLateralPosterolateralPosterolateralAnteriorAnterior

Extended NDExtended ND

2001 Classification:2001 Classification: RNDRND Modified RNDModified RND Selective ND (SND):Selective ND (SND):

SND (L.I-III/IV)SND (L.I-III/IV)SND (L.II-IV)SND (L.II-IV)SND (L.II-V)SND (L.II-V)SND (L.VI)SND (L.VI)

Extended NDExtended ND

Proposed by American HN Society and AAOHNS

Selective neck dissection Modified RND type 1,2,3.

Standard treatment options for management of lymph node:Radiation therapy alone or neck dissection:

N1 (0–2 cm).N2b or N3; all nodes smaller than 2 cm. (A combined surgical and radiation therapy approach should also be considered.)

Radiation therapy and neck dissection:

N1 (2–3 cm), N2a, N3.Surgery followed by radiation therapy, indications for which are as follows:

Multiple positive nodes.Contralateral subclinical metastases.Invasion of tumor through the capsule of the lymph node.N2b or N3 (one or more nodes in each side of the neck, as appropriate, >2 cm).

Radiation therapy prior to surgery:Large fixed nodes.

SURGICAL APPROACHESSURGICAL APPROACHES Trans-oral approachTrans-oral approach Lower cheek approachLower cheek approach Upper cheek approachUpper cheek approach mandibulotomymandibulotomy Visor flapVisor flap

Surgical approach depends Surgical approach depends onon

• • Tumor sizeTumor size • • Tumor siteTumor site • • Tumor locationTumor location • • Proximity to mandible or maxillaProximity to mandible or maxilla • • Need for neck dissectionNeed for neck dissection • • Need for reconstructive surgeryNeed for reconstructive surgery

SURGICAL MARGINSSURGICAL MARGINS

UK Royal college of pathologist guidelines:UK Royal college of pathologist guidelines: Clear margin: histological clearance Clear margin: histological clearance

>5mm>5mm Close margins: 1-5mmClose margins: 1-5mm Positive margin: <1mmPositive margin: <1mm Incidence higher in oral cavity cancer than Incidence higher in oral cavity cancer than

other HN sitesother HN sites.. Potentially due to complex anatomy and 3D Potentially due to complex anatomy and 3D

shape.shape.

Factors predicting positive Factors predicting positive marginmargin

Large tumour.Large tumour. Perineural spread.Perineural spread. Vascular permeation.Vascular permeation. Noncohesive invasive frontNoncohesive invasive front Cervical metastasisCervical metastasis

RADIOTHERAPYRADIOTHERAPY

Applications:Applications:

- Radical : early tongue, fom cancer- Radical : early tongue, fom cancer

- palliative : advanced total control not - palliative : advanced total control not possible: 20Gy x5 daily fractions x 1 possible: 20Gy x5 daily fractions x 1 week.week.

-combined therapy.-combined therapy.

-preoperative.-preoperative.

-postoperative.-postoperative.

RADIOTHERAPYRADIOTHERAPY

Small (T1/T2), superficial (<5mm Small (T1/T2), superficial (<5mm thickness) lesions of tongue & FOM: thickness) lesions of tongue & FOM: interstitial brachytherapy.interstitial brachytherapy.

Dose: 60 Gy/6days with iridium-192Dose: 60 Gy/6days with iridium-192

POST-OP RTPOST-OP RT

Indications:Indications:--presence of nodal disease with exptracapsular spread.presence of nodal disease with exptracapsular spread.

-presence of involved surgical margin-presence of involved surgical margin

-excision margin less than 5mm.-excision margin less than 5mm.

-stage III/IV.-stage III/IV.

-perineural or vascular invasion.-perineural or vascular invasion.

-poor differentiation.-poor differentiation.

-oral cavity primary.-oral cavity primary.

-multicentric primary.-multicentric primary.

->4 nodes positive.->4 nodes positive.

-soft tissue invasion.-soft tissue invasion.

-dysplasia or carcinoma insitu at resection margin.-dysplasia or carcinoma insitu at resection margin.

IMMUNOTHERAPYIMMUNOTHERAPY

Based on two principles:Based on two principles:

-immune system should recognise and destroy abnormal -immune system should recognise and destroy abnormal

cells.cells.

- tumor cells are poorly immunogenic and strongly - tumor cells are poorly immunogenic and strongly

immunosuppressive.immunosuppressive.

. Tumors downregulate antigen presenting molecule. Tumors downregulate antigen presenting molecule

. PGE2 produced by tumors inhibit lymphocyte . PGE2 produced by tumors inhibit lymphocyte

proliferation.proliferation.

. Cytokines produced by tumors inhibit lymphocytes. Cytokines produced by tumors inhibit lymphocytes

function.function.


IL-2 : stimulate growth, diffrentiation and IL-2 : stimulate growth, diffrentiation and survival of cytotoxic T cells.survival of cytotoxic T cells.

-systemic injection associated with sever -systemic injection associated with sever

reactionreaction..

- - Local injection in tumour: short half life Local injection in tumour: short half life requiring frequent injections.requiring frequent injections.

-IRX2 human cytokine mixture injected -IRX2 human cytokine mixture injected perilymphatically near tumour: in clinical perilymphatically near tumour: in clinical trialtrial


A trial of IRX-2 in patients with squamous cell carcinomas of the head and neck(Hadden J, et. al. Int Immunopharmacology. 2003 Aug;3(8):1073-81:

using immunotherapy with 10-20 days of perilymphatic injections of a natural cytokines mixture (NCM:IRX2;200 units IL2 equivalence)

Found - significant reduction in tumour mass. -increased area of leukocyte infiltration


Non-Specific Active Non-Specific Active ImmunomodulationImmunomodulation BCG vaccineBCG vaccine

Used to induce active, non specific stimulation Used to induce active, non specific stimulation of the immune systemof the immune system

Reports of increased tumor free survival Reports of increased tumor free survival which could not be substantiatedwhich could not be substantiated

Trials with other vaccines (strep pyogenes, Trials with other vaccines (strep pyogenes, trypanosoma cruzi, levamisole) show no trypanosoma cruzi, levamisole) show no benefits in long term survivalbenefits in long term survival


HPV VaccinesHPV Vaccines Estimated that 25% of HNSCC are HPV associatedEstimated that 25% of HNSCC are HPV associated

Tend to arise in younger patientsTend to arise in younger patients Lingual and palatine tonsilsLingual and palatine tonsils Occur predominantly in non smoker/drinkerOccur predominantly in non smoker/drinker Associated with a more favorable prognosisAssociated with a more favorable prognosis

HPV viral oncogenes E6 and E7 are consistently HPV viral oncogenes E6 and E7 are consistently expressed in HPV associated cancersexpressed in HPV associated cancers

Thought to integrate into the host DNA, and when Thought to integrate into the host DNA, and when expressed, bypass the regulation of cell proliferationexpressed, bypass the regulation of cell proliferation

Both protein and DNA vaccines targeting HPV DNA are Both protein and DNA vaccines targeting HPV DNA are currently in phase I and phase II trialscurrently in phase I and phase II trials

TARGETED THERAPYTARGETED THERAPY

Targeted therapy in head and neck cancer: state of the art 2007 and review of clinical applications( Langer CJ. Cancer 2008 Jun 15;112(12):2635-45:

-anti-EGFR monoclonal antibody(MoAb) cetuximab first targeted therapy to be developed

-single agent cetuximab confer clinical benefits in patient with cisplatin refractory metastatic disease.


Molecular targeted therapies in head and neck cancer - Molecular targeted therapies in head and neck cancer - An update of recent developments(Martin Goerner, et.al, An update of recent developments(Martin Goerner, et.al, Head & Neck Oncology 2010, 2:8):Head & Neck Oncology 2010, 2:8):

-anti-EGFR MoAbs :cetuximab , pantimumab, -anti-EGFR MoAbs :cetuximab , pantimumab,

zalutumumabzalutumumab

-EGFR targeted tyrosine kinase inhibitors: gefitinib, -EGFR targeted tyrosine kinase inhibitors: gefitinib,

erlotiniberlotinib

- EGFR & HER-2 combined tyrosine kinase inhibitors:- EGFR & HER-2 combined tyrosine kinase inhibitors:

lapatinib, BIBW-2992.lapatinib, BIBW-2992.

- VEGFR inhibitor: bevacicumab, sorafenib, sunitinib.- VEGFR inhibitor: bevacicumab, sorafenib, sunitinib.


Biologic Therapy in Head and Neck Cancer: A Road with Hurdles(Specenier P, et.al. ISRN Onco. 2012;2012:163752. Epub 2012 Jun 13):

- Yet to meet their primary endpoint. - result with EGFR directed tyrosine kinase

inhibitor disappointing. -other potential target include: insulin-like growth factor1

receptor(IGF-1R), insulin receptor(IR), histone deacetylases(HDAC), mammalian target of rapamycin(mTOR) , platelet derived growth factor receptor(PDGFR), heat shock protein90(HSP90), nuclear factor kappa-B(NF-kB), aurora A or B, and phosphatidylinositol3-kinase(PIK3CA).

Positive correlations of Oct-4 and Nanog Positive correlations of Oct-4 and Nanog in oral cancer stem like cells and high in oral cancer stem like cells and high grade oral squamous cell grade oral squamous cell carcinoma( Chiou SH, et.al, clinical cancer carcinoma( Chiou SH, et.al, clinical cancer research. 2008 Jul 1;14(13):4085-95:research. 2008 Jul 1;14(13):4085-95:

Enriched OC-SLC highly expressed Enriched OC-SLC highly expressed stem/progenitor cell markers and stem/progenitor cell markers and transporter (Oct-4, Nanog, CD117, Nestin, transporter (Oct-4, Nanog, CD117, Nestin, CD113, ABCG2) CD113, ABCG2)

GENE THERAPYGENE THERAPY

Gene therapy for oral squamous cell carcinoma: An overview( TR Saraswathi, et.al, Indian J Dent Res. 2007 Jul-Sep;18(3):120-3)

STRATEGIES:

-gene addition therapy: reconstitution of wild type p-53 -gene addition therapy: reconstitution of wild type p-53 function with p-53 expressing adenovirus-> led to inhibition of function with p-53 expressing adenovirus-> led to inhibition of SCC cell lines.SCC cell lines.

- antisense RNA therapy: introducing a remedial gene that - antisense RNA therapy: introducing a remedial gene that prevents expression of a specific defective gene: potential prevents expression of a specific defective gene: potential target E6 & E7 genes of HPV.target E6 & E7 genes of HPV.

- suicide gene therapy: introduction of a gene into a ce- suicide gene therapy: introduction of a gene into a ce ll ll inabling a prodrug to be activated into an active cytotoxic drug.inabling a prodrug to be activated into an active cytotoxic drug.

Recurrent lips & oral cavity cancerRecurrent lips & oral cavity cancer

Surgery is preferred, if radiation was Surgery is preferred, if radiation was used initially.used initially.

Surgery, radiation or combination if Surgery, radiation or combination if surgery used initially.surgery used initially.

Chemotherapy , but no increase in Chemotherapy , but no increase in survival demonstrated.survival demonstrated.

Other novel therapy methodOther novel therapy method

PROGNOSISPROGNOSIS

Location/thickness/depth of primary tumorLocation/thickness/depth of primary tumor StagingStaging Type of histologyType of histology GradingGrading Presence of perineural spreadPresence of perineural spread Mandibular invasionMandibular invasion Ln extension (Level, size, exptracapsular)Ln extension (Level, size, exptracapsular) Molecular markers (?)Molecular markers (?)

What happens after What happens after Treatment?Treatment?

Speech and Swallowing Therapy Speech and Swallowing Therapy Follow-up tests Follow-up tests Chemoprevention Chemoprevention Watch for new symptoms Watch for new symptoms General health considerations General health considerations

SummarySummary

The main problem of oral cancer is early The main problem of oral cancer is early detectiondetection

Surgery is still the most important Surgery is still the most important modality in management of oral cancer.modality in management of oral cancer.

Better understanding of molecular biology Better understanding of molecular biology of HNSCC. of HNSCC.

Bio-molecular markers can be used in the Bio-molecular markers can be used in the management of SCC oral cancer.management of SCC oral cancer.

High risk of second primary cancer, High risk of second primary cancer, Chemoprevention? Chemoprevention?

Health & Medicine

Oral cancer pwr.pnt