Lecture notes for medical students

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2. Learning Objectives

3. Learning Objectives
1. Introduction & History
2. Relevant Anatomy, Physiology
3. Aetiology
4. Pathophysiology
5. Pathology
6. Classification
7. Clinical Features
8. Investigations
9. Management
10. Prevention
11. Guidelines
12. Take home messages

4. Introduction & History.
•

5. Introduction & History.
• Oral cavity cancer accounts for up to 30-
40% of all malignancies in India.
• and is a significant worldwide health
problem.
• Most oral malignancies occur as squamous
cell carcinomas (SCCs)
• Despite remarkable advances in treatment
modalities, the 5-year survival rate has not
significantly improved over the past several
decades and still hovers at about 50-60%.

6. Introduction & History.
• Many oral SCCs develop from premalignant
conditions of the oral cavity
• Despite the general accessibility of the oral
cavity during physical examination, many
malignancies are not diagnosed until late
stages of disease.
• In order to prevent malignant
transformation of these precursor lesions,
multiple screening and detection techniques
have been developed to address this
problem.

7. Introduction & History.
• The early detection of cancer is of critical
importance because survival rates markedly
improve when the oral lesion is identified at
an early stage.

8. Premalignant conditions of Oral mucosa

9. Premalignant conditions of Oral mucosa
Definition
• Premalignant squamous lesions of the oral
cavity are areas of altered epithelium that
are at an increased risk for progression
to squamous cell carcinoma (SCC).
Not to be ignored, however, is the fact that up
to 50% of oral SCCs cases arise from
clinically normal mucosa.

10. Premalignant conditions of Oral mucosa
1. Leukoplakia
2. Erythroplakia
3. mixed erythroleukoplakia
4. palatal lesion of reverse cigar smoking
5. oral lichen planus
6. oral submucous fibrosis
7. discoid lupus erythematosus,
Hereditary disorders
7.dyskeratosis congenital and
8. epidermolysis bullosa.

11. Premalignant conditions of Oral mucosa
Other less-common conditions
• xeroderma pigmentosum
• dyskeratosis congenita,
• epidermolysis bullosa
• iron deficiency
• late-stage syphilis

12. Aetiology

13. Aetiology
• Idiopathic
• Congenital/ Genetic
• Nutritional Deficiency/excess
• Traumatic
• Infections /Infestation
• Autoimmune
• Neoplastic (Benign/Malignant)
• Degenerative / lifestyle
• Iatrogenic
• Psychosomatic
• Poisoning/ Toxins/ Drug induced

14. Aetiology
• Idiopathic
• Congenital/ Genetic
• Nutritional Deficiency/excess
• Traumatic
• Infections /Infestation
• Autoimmune
• Neoplastic (Benign/Malignant)
• Degenerative
• Iatrogenic

15. Pathophysiology

16. Risk Factors and Pathophysiology
1. Tobacco
2. Alcohol
3. HPV
4. areca nut/betel quid
5. immune suppression HIV] infection
6. chronic sun exposure (specifically for
cancer of the vermillion border of the lip),
and nutritional deficiency.
7. poor oral hygiene.

17. Risk Factors and Pathophysiology
• Industrial (metals [nickel, chromium], wood dust,
textiles, furniture, leather
• Chronic irritation (jagged teeth, luetic lesions,
gastroesophageal reflux disease)
• Asbestos
• Diet (vitamin A deficiency)
• Prior radiotherapy (to mucosa, salivary gland,
thyroid, skin)
• Iron deficiency (Plummer-Vinson syndrome)
• Mutagen-induced chromosome fragility

18. Risk Factors and Pathophysiology
• The use of tobacco has been well
established as a significant risk for the
development of oral squamous cell
carcinoma (SCC) and premalignant lesions
• Up to 80% of patients with oral SCC have
used tobacco products
• risk of developing malignancy is 5-9 times
greater for smokers than nonsmokers.
.

19. Risk Factors and Pathophysiology
• Alcohol use has also been implicated as a
risk factor for the development of oral SCC
and premalignant lesions.
• moderate to heavy drinkers have a 3-9 times
greater risk of developing cancer.
• heavy use of alcohol and tobacco combined
may convey a risk greater than 100 times
the general population.

20. Risk Factors and Pathophysiology
• The role of human papillomavirus(HPV) in
the development of oral premalignant
disorders and SCC continues to undergo
investigation.
• HPV types 16 and 18 may be found in
approximately 22% and 14% of
oropharyngeal tumors
• a recent study demonstrated HPV DNA in
17.6% of oral leukoplakic lesions and
19.7% of oral lichen planus samples. [

21. Risk Factors and Pathophysiology
• Despite the association between tobacco
and alcohol and the development of
persistent oral lesions, a definitive etiology
is seldom identified in many of these
lesions.
• the lack of distinctive histopathologic
features in many of the potentially
malignant disorders supports the
multifactorial pathogenesis of these lesions.

22. Classification

23. Classification
• The World Health Organization classifies
oral precancerous/potentially malignant
disorders into 2 general groups, as follows:
1. A precancerous lesion
2. A precancerous condition

24. Classification
• A precancerous lesion is “a
morphologically altered tissue in which oral
cancer is more likely to occur than its
apparently normal counterpart
1. leukoplakia,
2. erythroplakia,
3. the palatal lesions of reverse
smokers.

25. Classification
• A precancerous condition is “a
generalized state associated with
significantly increased risk of cancer-
1. submucous fibrosis
2. lichen planus,
3. epidermolysis bullosa,
4. discoid lupus erythematous.

26. Clinical Features
•

27. Clinical Features
• Demography
• Symptoms
• Signs
• Prognosis
• Complications

28. Demography

29. Demography
• prevalence rate ranges between 1% and 5%.
• Most affected patients are middle-aged or
elderly men.
• buccal mucosa, lower gingiva, tongue and
floor of mouth, with the remaining cases
distributed throughout the remainder of the
oral cavity.
• oral cancer is one of the most common
malignancies in Southeast Asia, accounting
for up to 30-40% of all malignancies in
India.

30. Demography
• increase in the incidence of tongue cancer in
young individuals (< 40 years old), from
3% in 1973 to approximately 6% in 1993,
• many of the affected individuals are without
traditional risk factors.
• traditional male predominance is less overt
in young individuals with oral SCC
• This trend is thought to be a reflection of
the general acceptance of social habits such
as smoking and drinking by both sexes.

31. Demography
• Overall, the rates of oral squamous
dysplasia and subsequent squamous cell
carcinoma (SCC) are decreasing, closely
paralleling the reduction in cigarette
smoking.

32. Leukoplakia
• Leukoplakia is defined by the World Health
Organization as a white lesion of the oral
mucosa that cannot be scraped off and
cannot be attributed to another definable
lesion
• The precise definition of leukoplakia
continues to undergo refinement in an
attempt to distinguish benign from
premalignant lesions,
• leukoplakia remains a clinical diagnosis of
exclusion.

33. Leukoplakia
Leukoplakia is subdivided into
1. homogeneous leukoplakia
1. nonhomogeneous leukoplakia (
erythroleukoplakia )
2. proliferative verrucous leukoplakia (PVL).

34. Leukoplakia
Nonhomogeneous leukoplakia is subdivided
into speckled and nodular types,
1. Speckled leukoplakia consists of flecks of
white on an erythematous base.
2. Nodular leukoplakia consists of small
surface excrescences, often on a red
background.

35. Leukoplakia
• Leukoplakia occurs most often in middle-
aged and older men and arises most
frequently on the buccal mucosa, alveolar
mucosa, and lower lip.
• lesions arising on the floor of mouth lateral
tongue and lower lip are the most likely to
harbor dysplasia or progress to malignancy.
• The rate of progression to malignancy has
been reported to be between 3.6% and
17.5%,

36. Leukoplakia
•

37. Leukoplakia
• 19.9% of leukoplakic lesions may
demonstrate some degree of dysplasia,
• 3.1% showing frank carcinoma.

38. Leukoplakia
• Risk factors for malignant transformation
of oral leukoplakia
1. advanced age
2. female sex
3. lesions of more than 200 mm2
4. nonhomogeneous lesions
5. higher-grade dysplasia.

39. Erythroplakia
• Erythroplakia is a clinical term used to
describe a fiery red patch that cannot be
clinically or pathologically distinguished as
any other definable disease.
• Similar to leukoplakia, the erythroplakic
lesion is considered as a diagnosis of
exclusion because numerous other disease
entities must be excluded before
erythroplakia is considered as the diagnosis.

40. Erythroplakia
• red macule or patch with a soft, velvety
texture most often occurring on the floor of
mouth, lateral tongue, retromolar pad, and
soft palate.
•

41. Erythroplakia

42. Erythroplakia
• Although far less common than leukoplakia,
erythroplakia is a worrisome clinical
condition that often harbors dysplasia.
• 51% of erythroplakic lesions have been
shown to demonstrate invasive squamous
cell carcinoma (SCC), with 40%
demonstrating carcinoma in situ, and 9%
exhibiting mild-moderate dysplasia.

43. Erythroleukoplakia

44. Proliferative verrucous leukoplakia
• Proliferative verrucous leukoplakia (PVL) is
a unique form of aggressive continuum of
leukoplakia and erythroplakia.
• Most patients with PVL are women, and
many do not have a history of tobacco use.
• irregular white patch or plaque with a
varying surface
• characterized by resistance to treatment,
recurrence, multifocal proliferation, and a
progression to carcinoma in up to 87% of
patients.

45. Proliferative verrucous leukoplakia

46. Palatal lesion of reverse smokers
• The palatal lesion of reverse smokers is
unique to individuals who place the lit end
of a cigarette inside the mouth.
• red, white, melanotic patch or papule.
• Up to 84% of palatal lesions have been
demonstrated to harbor dysplasia upon
histologic analysis

47. Oral submucous fibrosis
• Oral submucous fibrosis (OSF) is a chronic
progressive condition found predominantly
in people of Asian decent.
• OSF is considered to be the result of the use
of the Areca nut product with resultant
disruption of the extracellular matrix.
• The disease often manifests with diffuse
involvement of the oral cavity, pharynx, and
upper esophagus that appears clinically as
whitish mucosa lacking elasticity.

48. Oral submucous fibrosis
• Epithelial dysplasia has been described in 7-
26% of OSF tissues, and long-term studies
suggest a malignant transformation rate in
approximately 7% of these lesions.
• class I cytology (ie, characteristics
indicative of benign atypical cytologic
changes)

49. Lichen planus, discoid lupus
erythematous, and epidermolysis
bullosa
• Although classified as potentially malignant
conditions, the data regarding progression
to malignancy for these conditions is
controversial. Because of the difficulty in
classifying and clinically distinguishing the
varied lesions associated with these
conditions, the potential for malignant
transformation remains unclear.

50. Work-up and the Early Detection of
Oral Cancer

51. Work-up and the Early Detection of
Oral Cancer
• Oral examination
• Supravital staining
• Oral cytology
• Chemiluminescent light
• Tissue autofluorescence

52. Supravital staining
• Toluidine blue (TB) is an acidophilic dye
designed to stain acidic cellular components
such as DNA and RNA
• dysplastic tissue contains quantitatively
more DNA and RNA than nondysplastic
tissue.
• 1% solution is placed on the oral mucosa
and removed after 1-2 minutes with 2%
acetic acid. The clinician then examines the
oral mucosa for areas of increased cellular
staining.

53. Supravital staining
• TB staining may provide better demarcation
of lesion margins, may guide biopsy site
selection, and may be valuable in the
identification and visualization of lesions in
high-risk patients.
• cells undergoing inflammatory changes and
benign hyperplasia may also retain dye
leading to false-positive results.
• Overall, the sensitivity of TB staining
ranges from 0.78 to 1.00, and the specificity
ranges from 0.31 to 1.00.

54. Oral cytology
• a stiff brush to the oral mucosa with
enough pressure to induce pinpoint
bleeding, which ensures a full-thickness or
trans-epithelial tissue sample.
• cytomorphometry, DNA cytometry, and
immunocytochemical analysis.
• The use of oral cytology in the detection of
dysplastic lesions shows considerable
promise but has been limited thus far by
variable false-positive and false-negative
results.

55. Chemiluminescent light
• a diffuse chemiluminescent light source to
visualize abnormal oral mucosa not visible
under normal incandescent light.
• Under illumination, normal epithelium
absorbs the light (appearing light blue)
while abnormal tissue reflects the light
(appearing white, with sharper, distinct
margins).
• toluidine blue stain to aid in further lesion
assessment.

56. Tissue autofluorescence
• exposure of epithelial tissue to specific
wavelengths of light that results in the
excitation of cellular fluorophores and
emission of energy in the form of
fluorescence.
• With the disruption of normal tissue
morphology in dysplastic lesions, tissue
fluorescence is scattered and absorbed,
resulting in characteristic alterations in
color that can be visually interpreted.

57. Tissue autofluorescence
• Under excitation with the VELscope
device, normal mucosa emits a pale green
light, whereas abnormal mucosa appears
dark.
• The initial evidence suggests that the
VELscope may be useful as both an
adjuvant method of margin determination
during surgical procedures as well as a
screening technique to identify
premalignant lesions not visualized during
conventional examination.

58. Microscopic Findings
Squamous epithelial dysplasia
1. Abnormal architecture
2. Cytologic atypia.

59. Microscopic Findings
Abnormal architecture-
1. loss of cellular organization or
stratification,
2. basal cell layer hyperplasia
3. and loss of polarity,
4. dyskeratosis (single-cell keratinization)
5. keratin pearls deep within the epithelium
6. drop-shaped rete ridges

60. Microscopic Findings
Cytologic atypia-
1. nuclear enlargement,
2. increased nuclear-to-cytoplasmic ratio
3. variations in cellular and nuclear size and
shape
4. prominent nucleoli
5. nuclear hyperchromasia,
6. increased mitotic activity
7. atypical mitotic figures.

61. Microscopic Findings
grading schemes for dysplasia-
1. mild,
2. moderate,
3. severe
4. carcinoma in situ,

62. Prognosis

63. Prognosis
• Homogeneous leukoplakia transforms to
malignancy in only about 6% of cases.
• Nonhomogeneous leukoplakia and
erythroplakia, although less common, have
a much higher rate of dysplasia, with at
least 85% of cases showing severe dysplasia
or frank squamous cell carcinoma
• Proliferative verrucous leukoplakia (PVL),
in contrast, is a slowly progressive,
multifocal disease that eventually
progresses to SCC in almost all cases.

64. Investigations
• Laboratory Studies
– Routine
– Special
• Imaging Studies
• Tissue diagnosis
– Cytology
• FNAC
– Histology
– Germ line Testing and Molecular Analysis
• Diagnostic Laparotomy.

65. Differential Diagnosis

66. Differential Diagnosis
• Candidiasis
• Lichen planus
• Radiation atypia
• Reactive atypia

67. Management

68. Management
• Despite recognition of the premalignant
nature of oral dysplastic lesions, few, if any,
therapies to prevent cancer progression are
effective.

69. Management
• The treatment of leukoplakia consists of
excisional biopsy, when feasible,
• Multifocal advanced disease represents
approximately 10-15% of all oral
premalignant lesions and is rarely controlled
adequately with local therapy.
• Surgical excision can be used to remove
grossly evident disease

70. Management
• ionizing irradiation does not prevent the
progress of carcinogenesis. Ionizing
irradiation makes a sick mucosa sicker and
cannot be used again when the need may be
urgent.

71. Prevention

72. Prevention
• Diet richer in vegetables and fruits
• Avoid Tobacco
• Avoid alcohol consumption.
• Self examination.
• Good oral hygiene.

73. cancer-prevention tips.
• Don't use tobacco
• Avoid Alcohol
• Eat a healthy diet. ...
• Maintain a healthy weight and be physically
active. ...
• Protect yourself from the sun. ...
• Get vaccinated. ...
• Avoid risky behaviors. ...
• Get regular medical care.
• .

74. Early Detection
• Dental practitioners and dental care
professionals should remain vigilant for
signs of potentially malignant disorders and
oral cancer while performing routine oral
examinations.
• The mnemonic RULE
– Red
– Ulcerated
– Lump
– Extending for 3 or more weeks.
• Biopsy

75. Chemoprevention Agents
• Retinoids and vitamin A (beta carotene)
• Vitamin E
• Biochemoprevention
• Selenium
• Cyclooxygenase-2 (COX-2) inhibitors
• Tyrosine kinase inhibitors (TKIs)
• ONYX-015
• Protease inhibitors (PIs)

76. Chemoprevention Agents
Under Investigation
• EKB-569 - Family of drugs called EGFR
inhibitors
• Pioglitazone - Peroxisome proliferator–
activated receptor inhibitor
• Ad5CMV - Targets the TP53 gene
• Polyphenols of pomegranate juice
• Curcumin analogs
• Erlotinib, an epidermal growth factor
receptor (EGFR) tyrosine kinase inhibitor

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