1. Comprehensive review of
malignancies of Lips and Oral
Cavity
DR Kamlesh K. Dubey
Deptt. Of Otorhinolaryngology
AIIMS, New Delhi

2. Cellular system of Oral Cavity
Human squamous cell epithelium: important
role as barrier against- mechanical,
physical, pathological injury.
Limited availability of well defined culture
system for studying oral epithelial cell
biology.
Various molecular markers: for early
diagnosis

3. 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

5. 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

6. Leukoplakia

7. Erythroplakia

8. 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

11. 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.

12. Cancerous lesion of Lips& Oral
cavity
 Minor salivary gland tumor:
-in the glands lining the oral cavity
-adenoidcystic ca, mucoepidermoid ca,
adenocarcinoma.
-Sarcoma

14. 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

15. INCIDENCE
Demographic 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 alveolus
Major cause: tobacco chewing
Majority of patients presented in stage III
Majority presented within 6 months of onset

16. Risk Factors
 Tobacco: About 90% of people with oral cavity
and oropharyngeal cancer use tobacco
 Alcohol: Drinking alcohol strongly increases a
smoker's 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

17. 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

18. 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

19. Relative Risk factors for Oral
Cancers
Habit Relative Risk %
 None  1%
 Betel nut Chewing  4%
 Smoking only  3-6%
 Betel chewing + Tobacco  8-15%
chewing
 Betel chewing + Smoking  4-25%
 Betel+Tobacco+smoking  20%

20. 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

21. 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

22. 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.

23. INHERITED RISK FACTORS
A review of inherited cancer syndromes and
their relevance to oral squamous cell
carcinoma (Prime SS, Thakker NS, et.al.
Oral oncology 2001 Jan;37(1):1-16:
examined genetic defects associated with
inherited cancer syndromes and their
relevance to oral cancer.
Defective DNA repair mechanism:
xeroderma pigmentosa, ataxia

24. INHERITED RISK FACTORS
 Defective DNA repair mechanism:
xeroderma pigmentosa, ataxia
telangiectasia, bloom syndrome, fanconi
syndrome
 Tumor suppressor gene(p53) defect: Li
Fraumeni syndrome.

25. 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.

26. 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.

27. MOLECULAR BIOLOGY
 Cytogenetic : chromosomes
3,5,8,11,17,18.
 Tumor suppressor genes inactivation:
p16,p21,p53,RB gene.
 Proto-oncogene activation:
cyclinD1/PRADD1.
 Growth factors /receptors overexpression:
EGF,EGF-R,TGF-ɑ,HER-2/neu,FGF,FGF-
R,PDGF).

28. 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

29. MOLECULAR PROGRESSION MODEL OF HNSCC
CARCINOGENESIS
Normal squamous mucosa
EGF, EGFR
Overexpression
Squamous hyperplasia
Telomerase activation p16 inactivation
Dysplasia
PRAD-1 amplification 3p deletion
p53 inactivation
Carcinoma in-situ
4q, 5q, 8p, 13q
deletion
Invasive carcinoma
Matrix metalloproteinase
Over-expression
Metastasis

30. 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 p16
tumor invasion- identified with p53, Ki67.
Study highlights value of immunostain for
p16 in identifying dysplastic lesion
Predictive importance of p53, Ki16 markers
in identifying aggressive form of tumour.

31. 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.

32. 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%

33. Symptoms
 a sore in the mouth that does not heal (most
common symptom)
 pain in the mouth that doesn't 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 doesn't go away
 Increased salivation

34. 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

35. Patient Workup
 History
 Clinical examination
 Investigations

36. Patient Workup
 Investigations :
Primary: photographs
incisional biopsy
FNAC
Orthopantogram
CXR
ECG
Routin blood investigations

37. Patient Workup
Investigations: for staging
- CT face + neck ± CT chest
- MRI
- USG of neck or primary ± USG guided
FNAC of suspicious lymphadenopathy
- PET

38. 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

39. STAGING OF THE DISEASE
American joint committee on cancer:
T , N ,M
Tx- primary tumour cannot be assessed
T0- No evidence of primary tumour
T1- ≤ 2cm in greatest dimension
T2- 4cm < 2cm> in greatest dimension
T3- > 4cm in greatest dimension

40. STAGING OF THE DISEASE
T4a- Oral cavity: tumour invades through
cortical bone, into deep(extrinsic) muscle of
tongue, maxillary sinus or skin.
Lips: cortical bone, inferior alveolar
nerve, floor of mouth, skin i.e. chin or nose.
T4b- involves masticator space, pterygoid
plates, skull base and/or encases internal
carotid artery

41. STAGING OF THE DISEASE
N stage:
Nx- regional lymph nodes can not be
assessed.
N0- no regional lymph node metastasis.
N1- metastasis in a single ipsilateral
lymph node ≤ 3cm in greatest dimension.
N2a- metastasis in a single ipsilateral LN
> 3cm but < 6cm in greatest dimension.

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

43. Stage Grouping
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T1, T2 N1 M0
T3 N0, N1 M0
Stage IV A T1, T2, T3 N2 M0
T4a N0, N1, N2 M0
Stage IV B Any T N3 M0
T4b Any N M0
Stage IV C Any T Any N M1

44. 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

45. 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

47. 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

48. TREATMENT
 Patient factors:
age, general medical condition,
performance status, occupation,
lifestyle(smoking/drinking)
socioeconomic considerations
previous treatment

49. TREATMENT
 Physician factors:
surgery, radiotherapy, chemotherapy
nursing & rehabilitation services,
dental, prosthetics, support services

50. Treatment
 Surgery
 Radiotherapy
 Chemotherapy
 Immunotherapy
 Targeted therapy
 Gene therapy

51. Treatment of Choice
 Stage I , II: single modality treatment is
effective and preferable.
 Stage III , IV: multimodal therapy is
essential

52. 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

53. Classification of ND
1991 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 ND
Proposed by American HN Society and AAOHNS

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

55. 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.

56. SURGICAL APPROACHES
 Trans-oral approach
 Lower cheek approach
 Upper cheek approach
 mandibulotomy
 Visor flap

57. Surgical approach depends
on
 • Tumor size
 • Tumor site
 • Tumor location
 • Proximity to mandible or maxilla
 • Need for neck dissection
 • Need for reconstructive surgery

58. 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

59. Factors predicting positive margin
 Large tumour.
 Perineural spread.
 Vascular permeation.
 Noncohesive invasive front
 Cervical metastasis

60. RADIOTHERAPY
 Applications:
- Radical : early tongue, fom cancer
- palliative : advanced total control not
possible: 20Gy x5 daily fractions x 1 week.
-combined therapy.
-preoperative.
-postoperative.

61. RADIOTHERAPY
 Small (T1/T2), superficial (<5mm
thickness) lesions of tongue & FOM:
interstitial brachytherapy.
 Dose: 60 Gy/6days with iridium-192

62. POST-OP RT
Indications:
-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.

63. 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.

64. 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

65. 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

66. 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

67. 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

68. 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.

69. 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.

70. 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).

71. 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)

72. 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

73. 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

74. 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 (?)

75. What happens after Treatment?
 Speech and Swallowing Therapy
 Follow-up tests
 Chemoprevention
 Watch for new symptoms
 General health considerations

76. 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?