describe about molecular biology of oral cancer

1. MOLECULAR BIOLOGY OF ORAL
CANCER
DR JAMEEL KIFAYATULLAH

2. CHALLENGES FACED IN ORAL CANCER
• The challenges we face as oral and
maxillofacial surgeons are:
• difficulty in predicting the capricious clinical
behavior of oral cancer
• recurrence at the primary site after resection
• cervical and distant metastasis
• the development of second primary oral
cancers

3. MOLECULAR APPROACH USES
Molecular approaches are clearly going to be
used
• to predict clinical behavior
• determine prognosis
• guide surgical treatment
• assist with tumor surveillance

4. Traditional histopathologic features
used to manage oral cancer
• Histopathologic evaluation of margins
• Tumor grading
• Tumor size
• Tumor thickness
• Invasive pattern
• Perineural invasion
• Molecular alterations in oral squamous cell
carcinoma
• Molecular analysis of surgical margins
• Field cancerization

5. WHEN TO TREAT NECK
• It is generally agreed that if the risk of cervical
metastasis is greater than 20%, treatment of
the neck is indicated
• For patients with head and neck SCC and stage
N0 neck status, treatment of the neck is
indicated if the probability of occult cervical
metastasis is greater than 20%.

6. When to treat neck
• surgical treatment of the neck is often
indicated for patients with T1N0 oral SCC
lesions

7. TUMOR THICKNESS
• Spiro and coworkers retrospectively evaluated
105 patients with tongue or floor of the
mouth SCC and found that a tumor thickness
of 2 mm or less carried a metastasis rate of
7.5% and a tumor thickness greater than 2
mm carried a metastasis rate of 38%

8. Tumor thickness
• Byers and colleagues evaluated 91 patients with
tongue SCC and attempted to correlate lymph node
metastasis with multiple preoperative and
intraoperative factors, including thickness of the
specimen; depth of muscle invasion; frozen margin
status; perineural, vascular, or lymphatic invasion;
histologic differentiation; and DNA ploidy. In this study,
the best predictors for nodal metastasis were greater
than 4 mm of muscle invasion, double DNA ploidy, and
histologic differentiation. DNA ploidy must be used
with other pathologic tumor characteristics to predict
cervical metastasis.

9. Invasive pattern
• Woolgar and Triantafyllou have concluded
that the pattern of invasion affects the
interpretation of margins and that even a
clear (ie, 5 mm) margin might be inadequate
in a case with widely separated clusters of
invading tumor cells. Despite these studies, an
evaluation of invasive pattern is generally not
used in clinical practice to guide treatment

10. Perineural invasion
• Some oral SCCs are neurotrophic, and expression
of nerve cell adhesion molecule (NCAM) on the
SCC is associated with perineural invasion
• most studies have demonstrated that perineural
invasion is a histopathologic feature that
correlates with increased local recurrence and
cervical metastasis
• The use of perineural invasion as an independent
factor to predict prognosis and recommend
treatment is unclear at this time.

11. Molecular alterations in oral squamous
cell carcinoma
• Oral cancer is a rare cancer in which biopsies can
be obtained at multiple different times as the
lesion progresses through premalignant phases to
cancer
• The available genetic models suggest that cells
are altered by inactivation of tumor suppressor
gene or activation of oncogenes . These genetic
changes produce a cellular growth advantage to
the altered cells, which expand to produce a
malignancy

12. Phenotype
• refers to the observable physical properties of
an organism; these include the organism's
appearance, development, and
behavior. Phenotypes also include observable
characteristics that can be measured in the
laboratory, such as levels of hormones or
blood cells.

13. Molecular analysis of surgical margins
• Intraoperative histologic analysis of surgical
margins after resection cannot detect
epithelial cells that appear phenotypically
normal but have undergone transformation at
the molecular level. Therefore, occult tumor
cells present in normal-appearing tissue can
lead to local recurrence

14. Molecular analysis of surgical margins
• There is clear molecular evidence of genetic
alterations in histologically normal margins
surrounding oral SCC
• Tumor suppressor genes, such as TP53,
provide a negative growth signal through cell
cycle arrest or apoptosis.

15. Molecular analysis of surgical margins
• A tumor suppressor gene can be inactivated
through a mutation or deletion or by being
bound to a viral or cellular protein. Such
inactivation can lead to uncontrolled SCC
growth. The p53 mutation is the most
common genetic event in human cancer
• Fifteen percent to 60% of oral SCCs have been
shown to contain p53 mutations

16. Molecular analysis of surgical margins
• Brennan and coworkers have demonstrated
that histologically normal surgical margins
that contain p53 mutations are associated
with much higher local recurrence rates.

17. Molecular analysis of surgical margins
• Using an assay based on the polymerase chain
reaction (PCR), which has the capacity to detect 1
mutant cancer cell among 10,000 normal cells
• the authors analyzed the surgical specimens to
determine whether microscopically occult
neoplastic cells could be identified in surgical
margins and lymph nodes obtained after
resection for 30 head and neck cancer cases. The
presence of a p53 mutation in the margin was
associated with a significantly increased
incidence of local recurrence

18. Molecular analysis of surgical margins
• Molecular analysis identified neoplastic cells
in 6 (21%) of 28 lymph nodes that initially
tested negative by traditional histopathologic
analysis. This study highlights the potential
utility of molecular margin analysis

19. Molecular analysis of surgical margins
• TP16 is a tumor suppressor gene located on chromosomal region
9p21. This gene, which is also known as CDKN2A, encodes a
protein, p16, that binds to cyclin-dependent kinases 4 and 6 and
prevents their association with cyclin D1. The cyclin-dependent
kinase-cyclin D1 complex inhibition prevents retinoblastoma
phosphorylation, leading to the inhibition of the cell cycle G1/S
transition. Deletions, point mutations, or promoter
hypermethylation inactivates the p16 gene and allows potentially
mutagenic DNA damage to escape repair before cell division
• Methylation of CDKN2A is a key mechanism leading to inactivation
of the gene
• This method of molecular margin analysis could facilitate more
precise and complete surgical resection of oral SCC and improve the
locoregional control rate

20. Field cancerization
• Field cancerization also called field defect or field
effect is a well-known process of transformation
of an existing precancerous lesion into a
malignancy.Oral field cancerization implies that
oral cancer does not arise as an isolated cellular
phenomenon, but rather as an anaplastic
tendency involving many cells at once that results
into a multifocal development process of cancer
at various rates within the entire field in response
to a carcinogen, such as in particular tobacco

21. Field cancerisation
• Slaughter and colleagues demonstrated that
the epithelium surrounding head and neck
cancer was abnormal, and 11% of patients
were found to have an independent area of
malignancy. The authors concluded that the
epithelial changes were likely extensive and
likely contributed to the development of a
malignancy

22. Genomics
Applications of microarrays
The strength of microarray technology is the
ability to evaluate the expression of tens of
thousands of genes within a specimen. In the
future, genomic technology is likely to be used
by clinicians to understand and predict the
clinical behavior of oral cancer

23. Proteomics
• The proteome is defined as all the proteins
encoded by the genome. Proteomics is the
study and mapping of the human proteome.
Proteomics represents a link between the
information from the Human Genome Project
and the use of that information to understand
and treat cancer

24. Proteomics
• Cancer is a consequence of genetic and
epigenetic alterations that lead to protein
dysregulation affecting cell division,
differentiation, immune recognition, tissue
invasion, and metastasis
• Clearly, for oral cancer, the identification of a
salivary protein or proteomic pattern would
significantly aid in the screening of patients at
risk for oral cancer

25. References
• Molecular Biology and Clinical Behavior of
Oral Cancer Brian L. Schmidt, DDS, MD, PhD