Comprehensive review ofmalignancies of Lips and Oral Cavity DR Kamlesh K. Dubey Deptt. Of Otorhinolaryngology AIIMS, New Delhi
Cellular system of Oral CavityHuman squamous cell epithelium: importantrole as barrier against- mechanical,physical, pathological injury.Limited availability of well defined culturesystem for studying oral epithelial cellbiology.Various molecular markers: for earlydiagnosis
EPIDEMIOLOGY Oral cavity: extends from vermillion border of lips to plane between junction of hard palate and soft palate. Include : oral cavity- buccal mucosa, tongue, gingiva, retromolar trigon, floor of mouth, hard palate High incidence in India, France, SE asia. 40% of HN cancer Age of onset 6-7th decade, sex ratio 3:1
Pre-Malignant Lesions Leukoplakia - chronic, white, verrucous plaque with histologic atypia Severity linked to the duration and quantity of tobacco and alcohol use Occur anywhere in the oral cavity Lip, tongue, or floor of the mouth lesions are prone for progression to SCC Erythroplakia - non-inflammatory erythematous plaque Analagous to intra-oral erythroplasia of Queyrat or SCC in situ Biopsies - severe dysplasia and areas of frank invasion
Pre-Malignant Lesions… Submucous fibrosis generalized white discoloration of oral mucosa with progressive fibrosis, painful mucosal atrophy and restrictive fibrotic bands individuals who chew betel quid, a concoction of tobacco, lime, areca nut and betel leaves Ultimately leads to trismus, dysphagia and severe xerostomia 5 - 10 % progress to SCC
Cancerous lesion of Lips& Oral cavity Lips –SCC, Melanoma, BCC(rare) Oral cavity: -- scc: 9/10 incidence --verrucous ca: <5% low grade, slow growing rarely metastasizes with tendency to invade deep tissue.
Cancerous lesion of Lips& Oral cavity Minor salivary gland tumor: -in the glands lining the oral cavity -adenoidcystic ca, mucoepidermoid ca, adenocarcinoma.-Sarcoma
Incidence Globally >300,000 people diagnosed/year Eighth most common malignancy India –upto 40% of all malignancies M>F Raising trend 6-7th decade Most of the people are dying because of ignorance
INCIDENCEDemographic and clinical profile of oral squamous cell carcinoma patients: a retrospective study ( Shenoi R, Sharma BK, et.al, Indian J Cancer. 2012 Jan;49(1):21-6:Most common site: mandibular alveolusMajor cause: tobacco chewingMajority of patients presented in stage IIIMajority presented within 6 months of onset
Risk Factors Tobacco: About 90% of people with oral cavity and oropharyngeal cancer use tobacco Alcohol: Drinking alcohol strongly increases a smokers risk of developing oral cavity and oropharyngeal cancer. Ultraviolet light: More than 30% of patients with cancers of the lip have outdoor occupations associated with prolonged exposure to sunlight. Irritation: Long-term irritation to the lining of the mouth caused by poorly fitting dentures
Risk Factors Cont… Poor nutrition: A diet low in fruits and vegetables is associated with an increased risk Mouthwash: Some studies have suggested that mouthwash with a high alcohol content Human papillomavirus (HPV) infection: Immune system suppression : Age: The likelihood of developing oral and oropharyngeal cancer increases with age, especially after age 35. Gender: Oral and oropharyngeal cancer is twice as common in men as in women
How tobacco affects Tobacco smoke contains >4000 chemicals, at least 60 shown to be carcinogens. Smoke less tobacco: main form: chewing, snuff at least 28 carcinogens found in smokeless form
How Alcohol affects Chronic alcohol exposure results in increased cancer incidence in animal model. Acetaldehyde , reactive oxygen species- main mutagen Acetaldehyde: directly binds to DNA, alters methyl transfer leading to hypomethylation leading to alerted gene products Alcohol promotes cytochrome P450- which increases activation of procarcinogens( tobacco, alcohol). Alcohol can act as solvent facilitating entry of carcinogens into cells
Recent study on role of alcohol 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 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 FACTORSA review of inherited cancer syndromes andtheir relevance to oral squamous cellcarcinoma (Prime SS, Thakker NS, et.al.Oral oncology 2001 Jan;37(1):1-16:examined genetic defects associated withinherited cancer syndromes and theirrelevance to oral cancer.Defective DNA repair mechanism:xeroderma pigmentosa, ataxia
INHERITED RISK FACTORS Relationship between ABO blood groups and oral cancer (Jaleel BF, et. al. Indian J Dental Research 2012 Jan;23(1):7-10: found that people with blood group A had 1.46 times higher risk of developing oral cancer as compared with other blood group.
INHERITED RISK FACTORS Allergies and risk of head and neck cancer (Michaud DS, et.al. Cancer Causes Control. 2012 Aug;23(8):1317-22. Epub 2012 Jun 19). Case control study Allergies have heightened Th2 immunity Had a 19% lower risk of HNSCC. Statistically significant for oropharyngeal cancer. HPV status does not confound or modify associations with allergies.
MOLECULAR BIOLOGY RAS family oncogene. Telomeres, telomerase, cell senescence Tumor immunology(role of TIL, CTL, IL- 2/4/6) Tumor invasion and metastasis: (endothelial proliferation:PGE2,TGFβ,FGF,VEGF),MM P
DNA 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 p16tumor 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 CHANGES Immunohistochemical p53, Ki16, hTERT in oral scc( Abraho AC et.al.Brazil oral research 2011 Jan-Feb;25(1):34-41: p53 positivity in 93.3% of PMD, 43.3% of OSCC, 80% OEH.
Site of oral cavity Tongue : 35% Floor of mouth: 30% Lower alveolus: 15% Buccal mucosa: 10% Upper alveolus/hard palate: 8% RMT: 2% Lips: lower-93%, upper-5%, commissure- 2%
Symptoms a sore in the mouth that does not heal (most common symptom) pain in the mouth that doesnt go away (also very common) a persistent lump or thickening in the cheek a persistent white or red patch on the gums, tongue, tonsil, or lining of the mouth a sore throat or a feeling that something is caught in the throat that doesnt go away Increased salivation
More Symptoms difficulty chewing or swallowing difficulty moving the jaw or tongue swelling of the jaw that causes dentures to fit poorly or become uncomfortable loosening of the teeth or pain around the teeth or jaw voice changes a lump or mass in the neck weight loss persistent bad breath
Patient Workup Investigations: for staging- CT face + neck ± CT chest- MRI- USG of neck or primary ± USG guided FNAC of suspicious lymphadenopathy- PET
INVESTIGATIONS FOR RECONSTRUCTION Allen’s test of vascular supply to hand if a radial forearm flap anticipated. MRA of leg vessels if composite fibula reconstruction anticipated. Colour Doppler of chest , abdomen if DCIA(deep circumflex iliac artery) free flap anticipated CAD/CAM models if complex composite reconstruction Dental impression for all maxillary tumours
STAGING OF THE DISEASEAmerican joint committee on cancer:T , N ,MTx- primary tumour cannot be assessedT0- No evidence of primary tumourT1- ≤ 2cm in greatest dimensionT2- 4cm < 2cm> in greatest dimensionT3- > 4cm in greatest dimension
STAGING OF THE DISEASE T4a- Oral cavity: tumour invades throughcortical bone, into deep(extrinsic) muscle oftongue, maxillary sinus or skin. Lips: cortical bone, inferior alveolarnerve, floor of mouth, skin i.e. chin or nose. T4b- involves masticator space, pterygoidplates, skull base and/or encases internalcarotid artery
STAGING OF THE DISEASEN stage: Nx- regional lymph nodes can not beassessed. N0- no regional lymph node metastasis. N1- metastasis in a single ipsilaterallymph node ≤ 3cm in greatest dimension. N2a- metastasis in a single ipsilateral LN> 3cm but < 6cm in greatest dimension.
STAGING OF THE DISEASE N2b- metastasis in multiple ipsilateral LNs,none > 6cm in greatest dimension. N2c- metastasis in B/L or C/L LNs, none >6 cm. N3- metastasis in a LN > 6 cm in greatestdimensionM stage: Mx- cannot be assessed, M0- nodistant metastasis, M1- distant metastasisi.
Stage GroupingStage 0 Tis N0 M0Stage I T1 N0 M0Stage II T2 N0 M0Stage III T1, T2 N1 M0 T3 N0, N1 M0Stage IV A T1, T2, T3 N2 M0 T4a N0, N1, N2 M0Stage IV B Any T N3 M0 T4b Any N M0Stage IV C Any T Any N M1
TREATMENT Treatment goals: to eradicate primary tumor and LN metastasis, to maintain function, cosmetic reconstruction Factors affecting choice of treatment: tumor factor patient factor resource factor
Treatment Goals for Cancer of the Oral Cavity • Cure of cancer • Preservation or restoration of form and function • Avoid or minimize sequelae of treatment • Prevent second primary cancers
TUMOR FACTORS AFFECTING TREATMENT • Site • Size (T stage) • Location • Multiplicity • Proximity to bone • Pathological features • Histology, grade, depth of invasion, tumor type • Status of cervical lymph nodes • Previous treatment
TREATMENT Patient factors: age, general medical condition, performance status, occupation, lifestyle(smoking/drinking) socioeconomic considerations previous treatment
Treatment of Choice Stage I , II: single modality treatment is effective and preferable. Stage III , IV: multimodal therapy is essential
TREATMENT SURGERY: Early stage T1/2No tumor: Wide excision +/ - ND High risk of locoregional recurrent (40%) Management of No Neck : High incidence of occult metastasis in the clinically No Neck (15-43%) Controversy : Observation or Surgery/Radiation Depend on primary site. Should be have minimal morbidity ELND if risk of occult meta >20%. (SND/SOHND). Locally advanced tumor: Combined modality treatment
Classification of ND1991 Classification: 2001 Classification: RND RND Modified RND Modified RND Selective ND: Selective ND (SND): Supraomohyoid SND (L.I-III/IV) Lateral SND (L.II-IV) Posterolateral SND (L.II-V) Anterior SND (L.VI) Extended ND Extended NDProposed by American HN Society and AAOHNS
Selective neck dissection Modified RND type 1,2,3.
Standard treatment options formanagement 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 approach depends on • Tumor size • Tumor site • Tumor location • Proximity to mandible or maxilla • Need for neck dissection • Need for reconstructive surgery
SURGICAL MARGINS UK Royal college of pathologist guidelines: Clear margin: histological clearance >5mm Close margins: 1-5mm Positive margin: <1mm Incidence higher in oral cavity cancer than other HN sites. Potentially due to complex anatomy and 3D
RADIOTHERAPY Applications: - Radical : early tongue, fom cancer - palliative : advanced total control not possible: 20Gy x5 daily fractions x 1 week. -combined therapy. -preoperative. -postoperative.
RADIOTHERAPY Small (T1/T2), superficial (<5mm thickness) lesions of tongue & FOM: interstitial brachytherapy. Dose: 60 Gy/6days with iridium-192
POST-OP RTIndications:-presence of nodal disease with exptracapsular spread.-presence of involved surgical margin-excision margin less than 5mm.-stage III/IV.-perineural or vascular invasion.-poor differentiation.-oral cavity primary.-multicentric primary.->4 nodes positive.-soft tissue invasion.-dysplasia or carcinoma insitu at resection margin.
IMMUNOTHERAPY Based on two principles: -immune system should recognise and destroy abnormal cells. - tumor cells are poorly immunogenic and strongly immunosuppressive. . Tumors downregulate antigen presenting molecule . PGE2 produced by tumors inhibit lymphocyte proliferation. . Cytokines produced by tumors inhibit lymphocytes function.
IMMUNOTHERAPY IL-2 : stimulate growth, diffrentiation and survival of cytotoxic T cells. -systemic injection associated with sever reaction. - Local injection in tumour: short half life requiring frequent injections. -IRX2 human cytokine mixture injected perilymphatically near tumour: in clinical trial
IMMUNOTHERAPY 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
IMMUNOTHERAPY Non-Specific Active Immunomodulation BCG vaccine Used to induce active, non specific stimulation of the immune system Reports of increased tumor free survival which could not be substantiated Trials with other vaccines (strep pyogenes, trypanosoma cruzi, levamisole) show no benefits in long term survival
IMMUNOTHERAPY HPV Vaccines Estimated that 25% of HNSCC are HPV associated Tend to arise in younger patients Lingual and palatine tonsils Occur predominantly in non smoker/drinker Associated with a more favorable prognosis HPV viral oncogenes E6 and E7 are consistently expressed in HPV associated cancers Thought to integrate into the host DNA, and when expressed, bypass the regulation of cell proliferation Both protein and DNA vaccines targeting HPV DNA are currently in phase I and phase II trials
TARGETED 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.
TARGETED THERAPY Molecular targeted therapies in head and neck cancer - An update of recent developments(Martin Goerner, et.al, Head & Neck Oncology 2010, 2:8): -anti-EGFR MoAbs :cetuximab , pantimumab, zalutumumab -EGFR targeted tyrosine kinase inhibitors: gefitinib, erlotinib - EGFR & HER-2 combined tyrosine kinase inhibitors: lapatinib, BIBW-2992. - VEGFR inhibitor: bevacicumab, sorafenib, sunitinib.
TARGETED THERAPY 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 in oral cancer stem like cells and high grade oral squamous cell carcinoma( Chiou SH, et.al, clinical cancer research. 2008 Jul 1;14(13):4085-95:Enriched OC-SLC highly expressed stem/progenitor cell markers and transporter (Oct-4, Nanog, CD117, Nestin, CD113, ABCG2)
GENE 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 function with p-53 expressing adenovirus-> led to inhibition of SCC cell lines. - antisense RNA therapy: introducing a remedial gene that prevents expression of a specific defective gene: potential target E6 & E7 genes of HPV. - suicide gene therapy: introduction of a gene into a cell
Recurrent lips & oral cavity cancer Surgery is preferred, if radiation was used initially. Surgery, radiation or combination if surgery used initially. Chemotherapy , but no increase in survival demonstrated. Other novel therapy method
PROGNOSIS Location/thickness/depth of primary tumor Staging Type of histology Grading Presence of perineural spread Mandibular invasion Ln extension (Level, size, exptracapsular) Molecular markers (?)
What happens after Treatment? Speech and Swallowing Therapy Follow-up tests Chemoprevention Watch for new symptoms General health considerations
Summary The main problem of oral cancer is early detection Surgery is still the most important modality in management of oral cancer. Better understanding of molecular biology of HNSCC. Bio-molecular markers can be used in the management of SCC oral cancer. High risk of second primary cancer, Chemoprevention?