Oral cancer is a malignant neoplasia which arises on the lip or oral cavity, is traditionally defined as an oral squamous cell carcinoma (OSCC), because in the maxillofacial area, 90% of cancers histologically originatefrom the squamous cells. It has different levels of differentiation and a propensity for lymph node metastasis.
- Squamous cell carcinoma.
- Malignant salivary gland tumors.
- Malignant melanoma.
- Neoplasms of bone and connective tissue.
- Maxillary antral carcinoma (or other neoplasms).
- Metastatic neoplasms (from breast, lung, kidney, stomach, or liver cancer).
- Langerhans’ cell histiocytoses.
- Kaposi’s sarcoma.
Etiology and major risk factors of oral cancer are:
- Tobacco contains potent carcinogens, including nitrosamines (nicotine), polycyclic aromatic hydrocarbons, nitrosodicthanolamine, nitrosoproline, and polonium.
- Important carcinogens in tobacco smoke are Aromatic hydrocarbon benz‑pyrene and the tobacco- specific nitrosamines (TSNs) namely 4‑(nitrosomethylamino)‑1‑(3‑pyridyl)‑1‑butanone (NNK) and N’‑nitrosonornicotine (NNN).
- Increase the permeability of oral mucosa producing an alteration in morphology characterized by epithelial atrophy, which in turn leads to easier penetration of carcinogens into the oral mucosa.
- Major metabolite of alcohol is acetaldehyde.
- Acetaldehyde interferes with the DNA synthesis and repair.
- Acetaldehyde induces sister chromatid exchanges and specific gene mutations.
- Acetaldehyde inhibits the enzyme 6‑methylguanitransferase which is responsible for repairing injuries caused by alkylating agents.
Diet and Nutrition
- The working group of International Agency for Research on Cancer (IARC) has affirmed that lowintake of fruits and vegetables predisposes to increased risk of cancer development.
- Certain micronutrients decrease the risk of oral cancer:
- Vitamins A (retinol), C (AA), and E (α-tocopherol); carotenoids (β-carotene);
- Β-carotene, retinol, retinoids, vitamin C (AA), and vitamin E (α-tocopherol) are antioxidants that reduces free radical reactions that can cause DNA mutations, changes in enzymatic activity, and lipidperoxidation of cellular membranes.
- It is a tea‑like beverage consumed in South America and in parts of Europe.
- Maté’s carcinogenicity is due to thermal injury, solvent for other chemical carcinogens, and presence of tannins and N‑nitroso compounds.
Viral Infections: Capable of hijacking host cellular apparatus and modifying DNA and the chromosomalstructures and inducing proliferative changes in the cells. Viruses implicated in oral cancer development are:
- HPV- 33.
- Epstein Barr Virus (EBV).
- Human herpes virus- 8 (HHV-8).
- HIV(increase the risk of OC).
Tertiary syphilis may predispose to the development of oral cancer along with other risk factors suchas tobacco and alcohol.
Candida possesses necessaryenzymes fromdietary substances to produce nitrosaminesand chemicals that have been implicated in carcinogenesis.
- Immunosuppressed individuals are more prone to develop oral cancers.
- Human immunodeficiency virus (HIV)develops Kaposi’s sarcoma and lymphomas.
- Exposure to excessive solar radiation/ultraviolet (UV) light-lip cancers.
- UV rays – cause actinic cheilitis which may transform to OSCCs.
- Sulfur dioxide, asbestos, pesticide exposures, and mists from strong inorganic acids and burning of fossil fuelscause cancers of posterior mouth, pharynx, and larynx.
Carcinogenesis is a complex, multi-step process in which genetic events within signal transduction pathways are subverted/altered resulting into enhancement of cell’s ability for proliferation, uncontrolled apoptosis or grow by invading locally or metastasizing to distant sites.
- 10% of all cancers have a strong hereditary component.
- Glutathione S-transferase M1 (GSTM1) null genotype is the most consistent polymorphic susceptibility marker for head and neck cancer including OC.
- The variant val allele of the CYP1A1 (Cytochrome P450, family 1, member A1) polymorphism is anotherconsistent susceptibility marker.
- ALDH1B and ALDH2 (Aldehyde dehydrogenase 2) genes also associated with HNSCC and have correlation withalcohol consumption.
Proto-oncogenes, Oncogenes and Genetic Alterations
- Genetic alterations define molecular basis of carcinogenesis which includes point mutations, amplifications, rearrangements, and deletions.
- Aberrant expression of epidermal growth factor receptor (EGFR), K-ras, c-myc, int-2, Parathyroid adenomatosis 1 (PRAD-1) and B-cell lymphoma (bcl) like oncogenes are associated with OC development.
- Over expression and amplification of cellular oncogene EGFR is found in a 7,12-Dimethylbenz(a)anthracene (DMBA) induced hamster cheek pouch malignant OC model.
- Transforming growth factor-alpha (TGF-α) promote neovascularization and mitogenesis.
Tumor Suppressor Genes
- Primary HNSCC harbour p53 mutation.
- Inactivation of p53 represents the most common genetic change in all human cancers.
- The most commonly deleted region in HNC is located at chromosome 9p21–22.
- Loss of chromosome 9p21 occurs in the majority of invasive tumors in head and neck cancer.
- Loss of p16 protein occur in most advanced pre-malignant lesions.
- Introduction of p16 or p16ARF into HNC cell lines result in potent growth suppression
- Loss of chromosome 17p is also frequent in most human cancer including OC.
- Genomic instability such as loss of hetrozygosity (LOH) and microsatellite instability (MSI) are associated with cancer.
- Chromosome 9p21 containing p16 tumor suppressor gene is frequently lost in HNSCC and oral preneoplasticlesions .
- Chromosome 3p14 contains the tumor suppressor gene fragile histidine triad (FHIT) as well as a common fragile site, FRA3B also found to be frequently deleted in early tumorigenesis and its deletion is associated withexposure to cigarette smoke.
- Loss of function of the tumour suppressor p53 can result in uncontrolled cell division and progressive genomic instability.
- Alterations in certain regions of chromosomes 3p, 9p, 17p and 18q are associated with the development of HNSCC.
- The major epigenetic modification in tumours is methylation.
- Changes in the methylation patterns play an important role in tumorigenesis.
- Epigenetic modifications are frequently connected with the loss of genetic expression and important for the multiple indispensable genetic events during carcinogenesis.
- Malignant progression takes place because these alterations can inactivate DNA repairing genes.
- Methylation patterns of p16, methylguanine-DNA methyltransferase (MGMT) and Death-associated proteinkinase (DAP-K) genes in smears of patients suffering from head and neck cancer showed abnormal hypermethylation pattern.
- Chromosomes 9p and 3p appear to be lost early, closely followed by loss of 17p. Mutations in p53 gene areseen in the progression of pre-invasive to invasive lesions.
There is increase p53 mutation in patients who were exposed to both tobacco and alcohol.
Dysplasia means alterations in the morphology and functions of a cell.
- Dysplastic lesions have been categorized as mild, moderate, or severe.
- Mild dysplasia has dysplastic cells that are limited to the basal layer of the epithelium.
- Moderate and severe dysplasiainvolves increasing changes in cellular morphology and increasing thickness of the epithelium.
It is a lesion in which abnormal cells involve the entire epithelium without invasion through the basement membrane.
Is a lesion in which abnormal cells disrupt the basement membrane and invade into connective tissue.
- Abnormal variation in nuclear size and shape (anisonucleosis and pleomorphism)
- Abnormal variation in cell size and shape (anisocytosis and pleomorphism)
- Increased nuclear/cytoplasmic ratio.
- Enlarged nuclei and cells.
- Hyperchromatic nuclei.
- Increased mitotic figures.
- Abnormal mitotic figures (abnormal in shape or location).
- Increased number and size of nucleoli.
Architectural (Tissue) changes:
- Loss of polarity
- Disordered maturation from basal to squamous cells.
- Includes top-to-bottom change of carcinoma in situ.
- Increased cellular density
- Basal cell hyperplasia.
- Dyskeratosis (premature keratinization and keratin pearls deep in epithelium)
- Bulbous drop shaped rete pegs
- Secondary extensions (nodules) on rete tips
Thickened epithelium, Hyperkeratosis, Normal maturation
Cell and nuclear pleomorphism,
Basal cell hyperplasia
Up to middle third
Cell and nuclear
Anisocytosis and anisonucleosis,
Increased and abnormal mitotic figures
Loss of polarity
Disordered maturation from basal to squamous cells
Increased cellular density
Basal cell hyperplasia
Basal cell hyperplasia
Up to the upper third
Cell and nuclear
Anisocytosis and anisonucleosis,Nuclear hyperchromatism,
Increased and abnormal mitotic figures,
Enlarged nuclei and cells,
Increased number and size of nucleoli,Apoptotic bodies.
Disordered maturation from basal to squamous cells.
Increased cellular density.
Basal cell hyperplasia
Dyskeratosis (premature keratinization and keratin pearls deep in epithelium).
Bulbous drop shaped rete pegs.
Secondary extensions (nodules) on rete tips.
All changes may be present
Loss of stratification
- Non healing ulcer with or without induration / nonhealing socket
- White patch with firm consistency.
- Red lesion or lesion with erythematous appearance (Erythroplasia).
- Abnormal lump in the mouth with increase in size.
- Exophytic/ulceroproliferative growth.
- Mass or lump in the neck and neighbouring regions (Lymph node enlargement).
- Mobility/ displacement/ non vital teeth/periimplantitis.
- Tooth pain and referral pain.
- Bleeding from the mouth.
TNM classification of lip and oral cavity carcinomas
Rules for Classification
The classification applies only to carcinomas of the vermilion surfaces of the lips and of the oral cavity, including those of minor salivary glands. There should be histological confirmation of the disease. The following are the procedure for assessment of the T, N and M categories:
- T category Physical examination and imaging.
- N category Physical examination and imaging.
- M category Physical examination and imaging.
Anatomical Sites and Subsites
Lip (ICD Coding)
- External upper lip (vermilion border) (C00.0)
- External lower lip (vermilion border) (C00.1)
- Commissures (C00.6)
- Buccal mucosa.
- Mucosa of upper and lower lips (C00.3,4).
- Cheek mucosa (C06.0).
- Retromolar areas (C06.2).
- Buccoalveolar sulci, upper and lower (vestibule of mouth) (C06.1)
- Upper alveolus and gingiva (upper gum) (C03.0)
- Lower alveolus and gingiva (lower gum) (C03.1)
- Hard palate (C05.0)
- Dorsal surface and lateral borders anterior to vallate papillae (anterior two-thirds) (C02.0,1)
- Inferior (ventral) surface (C02.2)
- Floor of mouth (C04).
Regional Lymph Nodes: The regional lymph nodes are the cervical nodes.
According to the Hermanek P Sobin LH (eds),TNM clinical classification (T: tumor; N: lymph nodes; M: metastasis)
Definition of the TNM staging
Primary Tumor (T)
Primary tumor cannot be assessed
No evidence of primary tumor
Carcinoma in situ
Tumour 2 cm or less in greatest dimension
Tumour more than 2 cm but no more than 4 cm in greatest dimension
Tumour more than 4 cm in greatest dimension
Lip: Tumour invades adjacent structure, eg. Through cortical bone, tongue, skin of neck.
Oral cavity: Tumor invades adjacent structures, e.g. through cortical bone, into deep (extrinsic) muscle of tongue, maxillary sinus, skin.
Regional lymph nodes (N)
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
Metastasis in a single ipsilateral lymph node, more than 3 cm but no more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension.
Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension.
Metastasis in a lymph node more than 6 cm in greatest dimension
Note: Midline nodes are considered ipsilateral nodes.
Distant Metastasis (M)
Presence of distant metastasis cannot be assessed
No distant metastasis.
(pTNM pathological classification: The pT, pN and pM categories correspond to the T, N, and M categories).
- Squamous cell carcinoma, the most common oral malignancy, may be defined as a malignant tumororiginating from surface epithelium.
- It is characterized initially by invasion of malignant epithelial cells into the underlying connective tissue with subsequent spread into deeper soft tissues, adjacent bone,local-regional lymph nodes and ultimately to distant sites such as the lung, liver, and skeleton.
- Squamous cell carcinoma appears initially as white orred (sometimes mixed) irregular patchy lesions of theaffected epithelium.
- With time, these lesions exhibitcentral ulceration; a rolled or indurated border, whichrepresents peripheral invasion of malignant cells; andpalpable infiltration into adjacent muscle or bone.
- Painmay be variable, and regional lymphadenopathycharacterized by rubbery-hard lymph nodes that maybe tethered to underlying structures may be present.
- Other clinical features include a soft tissue mass, paresthesia, anesthesia, dysesthesia, pain, foul smell, trismus, grossly loosened teeth, or hemorrhage.
- Large lesions can obstruct the airway, the opening of the eustachian tube (leading to diminished hearing), or the nasopharynx.
- Commonly involves the lateral border of the tongue.
- Common site of bone invasion is the posterior mandible.
- Lesions of the lip and floor of the mouth may invade the anterior mandible.
- Also seen on the tonsils, soft palate, and buccal vestibule.
- It is uncommon on thehard palate.
Periphery and shape
- Lesions may erode into underlying bone from any direction, producing polymorphous and irregular radiolucency.
- Invasion characterized most commonly by an ill-defined, non corticated border.
- If bone involvement is extensive, the periphery appears to have fingerlike extensions preceding a zone of impressive osseous destruction.
- In pathologic fracture borders show sharpened thinned bone ends with displacement of segments and an adjacent soft tissue mass.
- Squamous cell carcinoma in jaw lesions is totally radiolucent.
- Original osseous structure can be completely lost.
- Occasionally small islands of residual normal trabecular bone.
Effects on surrounding structures
- Widening of the periodontal ligament space.
- Loss of adjacent lamina dura.
- Teeth may appear to float in a mass of radiolucent soft tissue bereft of any bony support.
- Grossly displaced teeth from their normal position.
- Increase in the width and loss of the cortical boundary of inferior neurovascular canal.
- Also known as Primary intraosseous carcinoma, intra-alveolar carcinoma, primary intra-alveolar epidermoid carcinoma, primary epithelial tumor of the jaw, central squamous cell carcinoma, primary odontogenic carcinoma, intra-mandibular carcinoma, odontogenic carcinoma, central mandibular carcinoma.
- Primary intraosseous carcinoma is a squamous cell carcinoma arising within the jaw that has no original connection with the surface epithelium of the oral mucosa.
- Rare and may remain silent until they have reached a fairly large size.
- Pain, pathologic fracture, and sensory nerve abnormalities.
- More common in men.
- Affect fourth to eighth decade of life.
- Surface epithelium is invariably normal in appearance.
- Mandible is more commonlyinvolved mostly in the molar region
- Associated with remnants of the dentallamina, it originates only in tooth-bearing parts of thejaw.
Periphery and shape:
- Majority of lesions are ill-defined.
- Have rounded or irregular in shape.
- Osseous destruction and varying degrees of extension at the periphery.
- Pathologic fracture.
- Step defects.
- Thinned cortical borders.
- Internal structure.
- Truly radiolucent with very little residual bone left within the center of the lesion.
Effects on surrounding structures:
- Destruction of the antral or nasal floors, loss of the cortical outline of the mandibular neurovascular canal.
- Root resorption is unusual.
- Loss of both lamina dura and supporting bone, appears to be teeth floating in space.
Also known asepidermoidcell carcinoma and carcinoma ex-odontogeniccyst. Condition may arise from inflammatory periapical, residual, dentigerous, and odontogenic keratocysts.
- Pain may be characterized as dull and of several months’ duration.
- Swelling is occasionally reported.
- Pathologic fracture.
- Regional lymphadenopathy.
- If upper jaw is involved, sinus pain or swelling may be present.
- May occur anywhere where an odontogenic cyst is found.
- Mostly occur in the mandible.
Periphery and shape:
- Because the lesion arises from a cyst, the shape is often round or ovoid.
- Small lesion in a cyst wall, periphery may be mostly welldefined and even corticated.
- As the malignant tissue progressively replaces cystlining, the smooth border is lost or becomes ill-defined.
- Occurs chiefly in elderly men.
- 3% occurred on the lower lip, 3.3% on the upper lip and 8.3% on the labial commissures.
- 97% lesions occurred in men.
- Lesion begins on the vermilion border of the lip to one side of the midline.
- It often commences as a small area of thickening, induration and ulceration or irregularity of the surface.
- As lesionincreases in size, it may create a small crater like defect or produce an exophytic, proliferative growth of tumor tissue.
- Sometimes large fungating masses develop in short duration.
- Sometimes lesion may be only slowlyprogressive.
- Generally slow to metastasize.
- Lesion may develop without regional lymph node involvement.
- Metastasis usually ipsilateral and involvesthe submental or submaxillary nodes.
- Disease of the elderly,but it may occur in relatively young persons.
- Common sign is a painless mass or ulcer.
- It becomes painful, as it becomes secondarily infected.
- Begin as a superficially indurated ulcer with slightly raised borders and may proceed either to develop a fungating, exophytic mass or to infiltrate the deep layers of the tongue, producing fixation and induration.
- Lesion develops on the lateral border or ventral surface of the tongue.
- Lesions on the posterior portion of the tongue are of a higher grade of malignancy, metastasize earlier and have poorer prognosis.
- Metastatic lesions may be ipsilateral, bilateral, or because of the cross lymphatic drainage, contralateral inrespect to the tongue lesion.
- Average age is 57-67 years.
- Lesion appears as indurated ulcer of varying size situated on one side of the midline.
- May or may not be painful.
- Occur in the anterior portion of the floor.
- Early extension into the lingual mucosa of the mandible, mandible proper and into the tongue occurs.
- Lesion may invade the deeper tissues and may even extend into the submaxillary and sublingual glands.
- Induces a peculiar thickening or slurring of the speech.
- Metastases found in the submaxillary group of lymph nodes.
- Primary lesion near the midline shows contralateral metastases.
- Lesion is often a painful ulcerative, indurated and shows infiltration of deeper tissues.
- Sometimes lesions are superficial and appear to be growingoutward from the surface and known asexophytic orverrucous growths.
- Most commonsites of metastases are submaxillary lymph nodes.
- Occur in patients with age of 40-61 years.
- Males are more affected than females.
- Manifest as an area of ulceration which may be a purely erosive lesion or may exhibit an exophytic, granular or verrucous type of growth.
- It may or may not be painful.
- Lesion mostly arises in edentulous areas but may develop in a site in which teeth are present.
- Fixed gingiva is more frequently involved than the free gingiva.
- The proximity of the underlying periosteum and bone usually show early invasion.
- In the maxilla, gingival carcinoma often invades into the maxillary sinus, palate or into the tonsillar pillars.
- In the mandible it may extend into the floor of the mouth or laterally into the cheek or deep into thebone.
- Cancer of the mandibular gingiva metastasizes more frequently than maxillary gingiva.
- Metastases to either the submaxillary or the cervical nodes eventually occur.
- Manifests as a poorly defined, ulcerated, painful lesion on one side of the midline.
- It frequently crosses the midline, may extend laterally to include the lingual gingiva, posteriorly totonsillar pillar, uvula.
- Lesion may invade into the boneor occasionally into the nasal cavity.
- Infiltrating lesionsof the soft palate may extend into the nasopharynx.
- Metastases occur to regional lymph nodes.
- Dangerous disease.
- Swelling or bulging of the maxillary alveolar ridge, palate or mucobuccal fold.
- Loosening or elongation of the maxillary molars or swelling of the face inferior and lateral to the eye.
- Unilateral nasal stuffiness or discharge.
- In edentulous patients loosening of or inability to tolerate the prostheticappliance may occur.
- In floor of the sinus disease is associated solely with oral structures.
- If the medial wall of the sinus is involved, nasal obstruction may result.
- Involvement of the superior wall or roof produces displacement of the eye.
- Invasion of lateral wall produces bulging of the cheek.
- Metastases involve the submaxillary and cervical lymph nodes.
Various diagnostic modalities for oral cancer:
- Visual examination Excision biopsy and Histopathology.
- Oral brush biopsy (OralCDx).
- Toluidine blue.
- Light-based detection systems.
- Chemiluminescence (ViziLite Plus; Microlux/DL, Orascoptic-DK).
- Tissue fluorescence imaging (VELscope).
- Laser capture.
- Toluidine blue is an acidophilic meta chromatic dye which selectively stains acidic tissue components, thus staining DNA and RNA. As it binds to nucleic acids (DNA or RNA), it helps in better visualization of high risk areas especially with rapid cell proliferation of OSCCand premalignant lesions.
- Lugol’s solution is used for delineation of themalignant change which produces a brown black stainwhen the iodine reacts with the glycogen content.
- Developed in 1999.
- Brush biopsy collects cells from the full thickness of the oral epithelium.
- The brush biopsy is a chair-side, easy to perform, painless test.
- Can be used to evaluate any suspicious lesion including common small white and red oral lesions to rule out dysplasia.
- OralCDx® brush biopsy is an oral trans epithelial ‘‘biopsy” system that uses computer-assisted brushing.
- The OralCDx® technique appears to overestimate dysplastic lesions and produce a high number of false-positive results and has a low positive predictive value (PPV).
These are based on the assumption that the structural and metabolic changes that take place in the mucosa during carcinogenesis give rise to distinct profiles of absorption and refraction when exposed to different types of light or energy. There are basically two main systems of detection:
- Tissue fluorescence imaging.
- Chemiluminescence or reflective tissue fluorescence has been previously used as 1% acetic acid washes to detect the “acetowhite’’ areas for detection of premalignant and malignant conditions.
Two systems are available:
- Vizilite® (Zila Pharmaceuticals, Phoenix, AZ, USA).
- Microlux/DL® (AdDent Inc., Danbury, CT, USA).
- Patient must rinse the mouth with a 1% acetic acid solution followed by direct visual examination of the oral cavity using a blue–white light source.
- The 1% acetic acid wash is used to help remove the glycoprotein layer and may increase the visibility of epithelial cell nuclei by dehydration.
- ViziLite Plus uses a disposable chemiluminescent light packet.
- MicroLux unit offers a reusable, batterypowered light source.
- Normal cells absorb the light and have a bluish color, whereas the light is reflected by abnormal cells with a higher nucleus: cytoplasm ratio and by epithelium with excessive keratinization, hyperparakeratinization and/or significant inflammatory infiltrate, which appear acetowhite with brighter, more marked and more distinguishable borders.
- The principle of tissue autofluorescence is that some bio-fluorophores within tissue get excited and emitfluorescence when exposed to a light source of particular wavelength.
- System used: The VELscope® system
- The VELscope® system is a portable device which detects the loss of fluorescence in visible and non-visible high-risk oral lesions such as cancers and pre-cancers, by applying direct fluorescence.
- Under intense blue excitation light (400 to 460 nm), normal oral mucosa emits a pale green auto-fluorescence when viewed through the selective (narrowband) filter incorporated within the instrument.
- Abnormal tissue (cancer or pre-cancer), due to a disruption in the bio-fluorophores, do not reflect as much light and appear darker than the surrounding normal tissue.
- Laser micro dissection is a non-molecular, minimally disruptive method to obtain cytologically and/or phenotypically defined cells or groups of cells from heterogeneous tissues.
- It is a versatile technology and allows the preparation of homogenous isolates of specific subpopulations of cells from which RNA/DNA or protein can be extracted for RT-polymerase chain reaction (PCR), quantitative PCR, Western blot analyses, and mass spectro-photometry.
- DNA image cytometry measures ploidy status to determine the malignant potential of cells.
- After staining with Feulgen dye, the cytological samples are compared with a reference group of cells. A computer-assisted analysis has been recently designed to identify deviations of cellular DNA content. Genomic instability contributes towards cancer development, and abnormal DNA content may distinguish the dysplastic lesions that might progress to cancer.
The salivary tumor markers in oral cancer include genomic markers, transcriptome markers, protein markers and microbiota.
Salivary genomic markers
Salivary transcriptome markers
Salivary protein markers
Somatic mutations in tumor suppressor genes (p53)
Elevated levels of defensin-1
Significant increase in the levels of Porphyromonasgingivalis, Tannerella Forsythia and Candida albicans.
Significantly elevated levels of Bacteroidesmelaninogenica and Streptococcus mitis.
Presence of HPV and EBV
Loss of heterozygosity in chromosome 3p, 9q, 13q and 17p
Promoter hypermethylation of genes (p16, MGMT, or DAP-K)
Cyclin D1 gene amplification
Decrease in 8-oxoguanine DNA glycosylase, phosphorylated-Src and mammary serine protease inhibitor (Maspin)
Calcyclin, Rho GDP dissociation inhibitor
Microsatellite alterations of DNA
OAZ1 SAT (spermidine/ spermine N1-acetyltr ansferase)
CEA, carcinoantigen (CA19-9), CA128 Intermediate filament protein (Cyfra 21-1) RNS, 8-OHdG DNA damage marker LDH
H3F3A: H3 histone, family 3A, DUSP1: Dual specificity phosphatase 1, SCC-Ag: Squamous cell carcinoma antigen 2, IL: Interleukin, OAZ1: Ornithine decarboxylase antizyme 1, CEA: Carcino-embryonic antigen, RNS: Reactive nitrogen species, LDH: Lactate dehydrogenase, HPV: Human papilloma virus, EBV: Epstein–Barr Virus, CA: Cancer antigen
- Cell type and degree of differentiation.
- The site.
- The size.
- Location of the primary lesion.
- Lymph node status.
- Presence of bone involvement.
- Ability to achieve adequate surgical margins.
- Ability to preserve speech.
- Ability to preserve swallowing function.
- Physical and mental status of the patient.
- Thorough assessment of the potential complications of each therapy.
- Experience of the surgeon and radiotherapist.
- Cooperation of the patient.
- Surgery or radiation is used with curative intent in the treatment.
- Chemotherapy is an adjunct to radiation and surgery.
- T1 and T2 lesions may be treated either by surgery alone or by radiation alone.
- Advanced lesions may require combined therapy of surgery and radiations along with chemotherapy.
- Characteristic features of malignant lesions in plain radiographs include:
- Atrophy of cortical lamina.
- Osteolytic defects: both single and multilocular with an initial osteosclerotic capsule.
- In later stages, the ridges of bone defects become sharp and the teeth lose their bony support at the site of infiltration.
- On panoramic radiographs, the involvement of the facial bones cannot be assessed.
- Not helpful in assessing soft tissues.
- Detect the primary tumors as well as their local bone infiltration.
- Contrast-enhanced CT can accurately determine lymph node metastases.
- Multi-detector CT (MDCT) can precisely determine the boundaries of the tumor.
- MDCT can very precisely determine the involvement of the inferior alveolar nerve.
Perfusion computed tomography
- By assessing perfusion of the tumor site, it is possible to better evaluate the involvement of the surrounding tissues.
- The tumor is characterized by an increased blood volume (BV) and blood flow (BF) in comparison to healthy tissues. This results from neoangiogenesis in the tumor.
- Perfusion CT is superior to CT in regard to the assessment of muscle involvement.
- The sensitivity of CTP in detecting local lymph node metastases is 67%.
- CTP can distinguish between nonspecific changes after radiation therapy or chemotherapy and local recurrence.
Cone beam computed tomography (CBCT)
- More accurate than panoramic radiography and comparable to MRI, CT and bone scintigraphy.
- Detects osteolysis.
- CBCT is limited by a poor assessment of soft tissues.
CT fluoroscopy-guided biopsy
- CT fluoroscopy is a minimally invasive imaging technique that enables a real-time assessment.
- It can be used for taking biopsies of oral cancers.
Magnetic resonance imaging (MRI)
- MRI enables the detection of very small lesions, assessment of local spread of the tumor, planning surgery, evaluation of complications that can occur during and after surgery.
- Determine the involvement of local soft tissues, bone marrow and bones as well as vessels and nerves.
- MRI can effectively detect both local lymph node metastases and distant metastases of oral cancers.
- Can differentiate between metastases and can assess the size of lymph node clusters.
- After diagnosing oral cancer, MRI should be used in order to assess a possible involvement of the neck and chest.
- In cases of micro metastases in the lymph nodes, DWI-based MRI and hybrid methods can be helpful.
- Can assist in planning the scope of resection and further reconstruction, graft implantation, and differentiation between disease recurrence and scars after surgery.
Diffusion-weighted imaging MRI (DWI-MRI)
- DWI detects local lymph node metastases.
- DWIMRI of lymph nodes smaller than 1 cm is superior to MRI.
- DWI can precisely detect structures involved by cancer.
- It can also differentiate between reactive and metastatic lymph nodes.
- It should be used for lymph node assessment before surgery.
- DWI can be helpful in assessing early response of the tumor to chemotherapy (as early as after 1–2 cycles of chemotherapy).
Dynamic contrast-enhanced magnetic resonance imaging (DCEMRI)
- DCE-MRI is a valuable tool in the diagnosis of oral cancer.
- Dynamic MRI after administration of a contrast agent enables the assessment of tumor perfusion and extra-lymphatic dissemination before surgery.
- Based on DCE-MRI, the microvasculature and perfusion of the tumor can be evaluated, which can help predict the outcome.
Single-photon emission computed tomography (SPECT)
- SPECT allows for mapping metabolic activity of the tumor with the use of gamma radiation.
- The sources of radiation are isotopes such as 3-D 99mTcDPD (technetium-dicarboxypropan SPECT) or 99mTechnetium methoxy isobutyl isonitrile (MIBI).
- In the early stages of oral cancer, sentinel lymph node biopsy (SLNB) is of high importance.
- Techniques for the detection of sentinel nodes includes:
- Lymphoscintigraphy before surgery.
- Injection of the patent blue dye.
- Freehand SPECT can determine the location of the sentinel node, its distance from the skin, relation to the surrounding structures and evaluates the flow of lymph into the sentinel node.
Positron emission tomography (PET)
- PET with 18F-fluorodeoxyglucose evaluates tissue metabolic activity.
- It is used when planning adjuvant treatment and predicting survival without recurrence.
- It can be used for the detection of metastatic lymph nodes.
- It allows for an estimation of the risk of recurrence.
- PET is used to look for the primary tumor site when metastases are found earlier.
- PET is also routinely used for detecting distant metastases of known primary tumors.
- PET is recommended in stage IV and should not be used as the method of choice in earlier stages.
- Ultrasonography is used to evaluate superficial lesions, lymph nodes and to guide needle aspiration biopsies (NAB).
- NAB is used in order to confirm metastatic lymph nodes.
- It can show an increased vascularity within the tumor (blood flow), microvascular changes, size of the lesion and its thickness and the distance between mucous membrane and the front of the tumor.
- Can be helpful is assessing lymph nodes following a radical surgical resection with or without adjuvant radiation therapy
- It cannot detect lesions beyond mucous membrane.
- Chemoradiation: Chemo typically combined with radiation therapy may be used instead of surgery as the main treatment for some cancers. This is called chemoradiation.
- Adjuvant chemotherapy: Chemo (combined with radiation therapy) may be given after surgery to try to kill any small deposits of cancer cells that may have been left behind. This is known as adjuvant chemotherapy.
- Neoadjuvant or induction chemotherapy: Chemo (sometimes with radiation therapy) may be used to try to shrink some larger cancers before surgery. This is called neoadjuvant or induction chemotherapy.
- Chemo with or without radiation therapy:Can be used to treat cancers that are too large or have spread too far to be removed by surgery. The goal is to slow the growth of the cancer for as long as possible and to help relieve any symptoms the cancer is causing.
The chemo drugs used most often for cancers of the oral cavity and oropharynx are:
- 5-fluorouracil (5-FU).
- Paclitaxel (Taxol®).
- Docetaxel (Taxotere®).
Other drugs that are used less often include:
A chemo drug may be used alone or combined with other drugs. Combining drugs can often shrink tumors better, but tend to cause more side effects.
The side effects of chemo depend on the type and dose of drugs given and how long they are taken. Side effects can include:
- Hair loss.
- Mouth sores.
- Loss of appetite.
- Nausea and vomiting.
- Low blood counts.
Chemo can affect the blood-producing cells of the bone marrow, leading to low blood cell counts. This can lead to:
- Increased chance of infections (due to low white blood cell counts).
- Easy bruising or bleeding (due to low blood platelet counts).
- Fatigue (due to low red blood cell counts).
There are three main goals for chemotherapy (chemo) in cancer treatment:
Cure: If possible, chemo is used to cure cancer, meaning that the cancer is destroyed – it goes away and doesn’t come back.
Control: If cure is not possible, the goal may be to control the disease. Chemo is used to shrink tumors and/or stop the cancer from growing and spreading. This can help the person with cancer feel better and live longer.
Palliation: Chemo can also be used to ease symptoms caused by the cancer. This is called palliative chemotherapy or palliation.
Factors to consider when choosing which drugs to use include:
- The type of cancer.
- The stage of the cancer (how far it has spread).
- The patient’s age.
- The patient’s overall health.
- Other serious health problems (such as heart, liver, or kidney diseases).
- Types of cancer treatments given in the past.
Depending on the drug(s) to be given, there are different ways to determine chemo doses. Most chemo drugs are measured in milligrams (mg).
- The overall dose based on a person’s body weight in kilograms (1 kilogram is 2.2 pounds). For instance, if the standard dose of a drug is 10 milligrams per kilogram (10 mg/kg), a person weighing 110 pounds (50 kilograms) would get 500 mg (10 mg/kg x 50 kg).
- Doses are also determined based on body surface area (BSA), which are calculated using height and weight. BSA is expressed in meters squared (m2).
- Dosages of some drugs may also be adjusted for people who:
- Are elderly.
- Have poor nutritional status.
- Are obese.
- Have already taken or are currently taking other medicines.
- Have already had or are currently getting radiation therapy.
- Have low blood cell counts.
- Have liver or kidney diseases.
- Chemotherapy drugs target cells at different phases of the process of forming new cells, called the cell cycle.
- Cancer cells tend to form new cells more quickly than normal cells and this makes them a better target for chemotherapy drugs. Normal cells are also damaged along with the cancer cells, and this causes side effects. It is necessary to find a balance between killing the cancer cells (in order to cure or control the disease) and sparing the normal cells (to lessen side effects) at each time chemo is given.
Surgery may be the primary treatment or may be part of combinedtreatment with radiation therapy.
- Tumors involving bone.
- When the side effects of surgery are expected to be less significant than those associated with radiation.
- Lesions that lack sensitivity to radiation.
- Recurrent tumor in areas that have previously received a maximum dose of radiotherapy.
- In palliative cases to reduce the bulk of the tumor and to promote drainage from a blocked cavity (eg, antrum).
- Incomplete excision.
- Inadequate margins of resection.
- Tumor seeding in the wound.
- Unrecognized lymphatic or hematogenous spread.
- Neural invasion/ perineural spread.
- Tumor resection
In a tumor resection, the entire tumor and a margin (edge) of normal-looking tissuearound it is removed (resected). The margin of normal tissue is taken out to reduce thechance of any cancer cells being left behind.
- Mohs micrographic surgery (for some cancers of the lip)
Some cancers of the lip may be removed by Mohs surgery, also known as micrographicsurgery. The tumor is removed in very thin slices. Each slice is looked at right awayunder the microscope to see if there are cancer cells. Slices are removed and examineduntil no cancer cells are seen.
- Glossectomy (removal of the tongue)
Glossectomy may be needed to treat cancer of the tongue. For smaller cancers, onlypart of the tongue (less then 1/3) may need to be removed (partial glossectomy). Forlarger cancers, the entire tongue may need to be removed (total glossectomy).
- Mandibulectomy (removal of the jaw bone)
- For a mandibulectomy (or mandibular resection), the surgeon removes all or part of thejaw bone (mandible). This operation may be needed if the tumor has grown into the jawbone.
- If a tumor near the jaw is hard to move, it often means that the cancer has grown into the jaw bone.
- If the jaw bone looks normal on imaging tests and there’s no evidence the cancer hasspread there, the bone may not need to be cut all the way through. In this operation,also known as a partial-thickness mandibular resection or marginal mandibulectomy.
If cancer has grown into the hard palate (front part of the roof of the mouth), all or part ofthe involved bone (maxilla) will need to be removed. This operation is called a maxillectomy or partial maxillectomy.
- Robotic surgery
Increasingly, trans-oral robotic surgery (TORS) is being used to remove cancers of thethroat (including the oropharynx).
- Neck dissection
- Cancers of the oral cavity and oropharynx often spread to the lymph nodesin the neck.
- Removing these lymph nodes (and other nearby tissues) is called a neck dissection orlymph node dissection and is done at the same time as the surgery to remove the maintumor.
- In a partial or selective neck dissection only a few lymph nodes are removed.
- For a modified radical neck dissection, most lymph nodes on one side of the neckbetween the jaw bone and collarbone are removed, as well as some muscle andnerve tissue.
- In a radical neck dissection, nearly all nodes on one side, as well as even moremuscles, nerves, and veins are removed.
- Reconstructive surgery
- Removing larger lesions may cause defects in the mouth, throat, or neck that will need to be repaired.
- Sometimes a thin slice of skin, taken from the thigh or other area, can be used to repaira small defect. This is called a skin graft.
- To repair a larger defect, more tissue may be needed. A piece of muscle with or withoutskin may be rotated from an area close by, such as the chest (pectoralis major pedicle flap) or upper part of the back (trapezius pedicle flap).
Radiation therapy may be administered with intent to cure, as part of a combined radiation-surgery and/or chemotherapy management, or for palliation.
In palliative care, radiation may provide symptomatic relief from pain, bleeding, ulceration, and oropharyngeal obstruction.
Radiation kills cells by interaction with water molecules in the cells, producing charged molecules that interact with biochemical processes in the cells. DNA is disrupted, and chromosomal damage occurs. The affected cells may die or remain incapable of division.
- Dose per fraction.
- Number of fractions per day.
- Total treatment time.
- Total dose of radiation.
Ionizing radiation does not distinguish between cancerous andnormal tissues per se. Therefore, successful radiotherapy treatmentdepends on optimizing the dose to the tumor and minimizingdamage to normal tissue, a delicate balance called the therapeuticratio.
There are three major modalities of radiation therapy:
- Teletherapy or external beam radiation
- Radioactive isotopes.
It involves the delivery of electromagnetic radiation (e.g.X-rays, gamma rays) or particulate radiation (e.g. electrons,protons) from a linear accelerator or radionuclide source, such as60cobalt kept at a distance away from the patient.
- Kilovoltage Therapy
- Superficial X-rays (50-150 kV).
- Orthovoltage X-rays (150-300 kV).
- Megavoltage Therapy
- Cobalt gamma rays (1.17-1.33 mV)
- Linear accelerators (4-25 mV) (1 mV = 1000 kV).
- Hot-cathode X-ray tubes developed by WilliamCoolidge, which produced energies in 200 kV range.
- Treatment with these tubes was initially termed Deep Roentgen therapy and later called orthovoltage XRT.
- It was used to treat superficially situated skin tumors.
- The machinery was relatively inexpensive.
- It was simple in design.
- It demonstrated straightforward principles of operation.
- This unit has a 60Cobalt source surrounded by protective shieldingwith a shutter system, which allows the patient to be treated through an adjustable collimeter.
- 60Cobalt is an isotope produced bybombarding its stable form 59Co with neutrons.
- 60Cobalt then attempts to gain stability by the emission of gamma rays of 1.17 mV to 1.33 mV.
- It has decay half life of 5.26 years.
- The treatment times have to be adjusted monthly.
- 60Cobalt units delivered the dose maximum below the skin surface of the patient resulting indramatically reduced skin reactions.
- It requires less servicing than a linear accelerator, except only monthly calibration.
- The relatively low cost has made them the favored source.
- The unit cannot be turned off.
- It should always be kept shielded.
- In an accelerator, electrons produced from an electron gun are injected into a waveguide insynchrony with a radiofrequency wave produced from a magnetron.
- The electrons are accelerated to high speeds in the waveguide andare then fed into the head.
- Thesemachines normally operate at 4 to 25 mV range.
- It has sophisticated computerized treatment delivery system.
- It can deliver tumoricidal doses of radiation to customizedtreatment volumes in any anatomical site.
- It is expensive to maintain than cobalt units.
- It requires daily calibration.
- Linear accelerators replaced 60Cobalt units due to variable dose rates.
- Enhanced skin sparing in comparison to 60Cobalt units.
- Multimodalities available in same treatment machine.
- A narrower penumbra than that produced by 60Cobalt units.
- Network capabilities between accelerator and the treatmentplanning computer, simulator, CT/MRI suites, other treatmentmachines and the automated patient booking system.
- First proposed by Dr G Forsell in 1931.
- The prefix ‘brachy’ simply mean a short range delivery ofradiation.
- Brachytherapy is a method of radiation therapyin which an encapsulated source or a group of such sources isutilized to deliver gamma or beta radiation at a distance of up to afew centimeters either by surface, intracavitary or interstitial application.
- Source consists of small amounts of radionuclide that are totally encapsulated by a non-toxic and inert material, such as stainless steel or platinum.
- Radioactive sources come in the form of small needles, wires, rods or spheres.
- Commonly used isotopes are Radium226, Cesium137, Iridium192 and Iodine.
- A dose of 65 Gyover 6-7 days is given when it is used as the sole treatment.
- A high dose of radiation can be delivered directly to the tumorsparing surrounding normal tissue.
- Treatment time is short.
- It can be used only in selected cases especially in the earlystage of disease at accessible sites.
- It requires anesthesia and excellent expertise.
- It is an invasive procedure.
Interstitial Brachytherapy:In this, radioactive sources areinserted into the tumor via surgical intervention. Eg.carcinoma of tongue and buccal mucosa.
Mold Therapy:The radiation source is placed into a plasticmold on the patient’s skin or mucous membrane. The radiationdose from a mold falls off rapidly and is therefore ideal fortreating superficial tumors. E.g carcinoma of hardpalate and skin cancer.
Intracavitary Brachytherapy:Radioactive isotopes are keptinside a body cavity. E.g Carcinoma of nasopharynxand cervix, oesophageal and lung tumors.
Depending upon the loading, brachytherapy is classified into:
Preload: 266Radium was used for its very long half life of 1620 years. It had numerous disadvantages and hence now days, Caesium is used.
Afterload techniques: It may be conventional (manual) or remote (automatic)
First hollow metal or plastic tubes are inserted into the tumor. Theradiograph is taken to verify the position of the tubes and if theposition is correct then only sealed radioactive sources are insertedinto the tube manually.
The plastic tubes are positioned within the patient as described above but source transfer is then conducted automatically with the help of machine. After the treatment, the source goes back into the machine.
It is administered using high-dose rate (HDR- 1200 or more cGy/hr), medium-dose rate (MDR-200-1200cGy/hr) or rarely, low-dose rate (LDR-40-200 cGy/hr) equipment.
Radioisotope is either injected or taken as a drink to treat tumors. Commonly used isotopes are Iodine-131, Phosphorous-32, Yittrium-90.
- The earliest treatments were generally delivered as single large exposures, by placing low-energy cathode ray tubes or radiumfilled glass tubes in close proximity to tumors.
- The result was extensive normal tissue damage with rare incidence of cure of tumors.
- Fractionation of the total dose of radiation helps in minimizing normal tissue reaction.
Conventional fractionation is the application of 180 to200 cGy in single daily dose and five fractions per week to a totaldose of 40 to 70 Gy (4-7weeks) depending upon the type oftumor (1 Gy = 100 cGy).
- In this two or more fractions of radiotherapy dose (115-120 cGy) are given per day with overall treatment time similar to that of conventional fractionation.
- Hyperfractionation helps in increasing the total dose without increasing the late reactions.
- Fractions are separated by atleast six hours, based on the biological observation that most sublethal damage repair occurs within six hours.
- It refers to delivering the same total dose over a shortened treatment time, most often through the use of twice or thrice daily fractions.
- It is done in an effort to reduce the repopulation of tumor cells (tumor-cell regeneration) in rapidly proliferating cancers.
It is a variant of accelerated fractionation wherein treatment isdelivered once daily for the first 3.5 weeks and then twice dailyduring the final 2 to 2.5 weeks, when tumor cells can begin torepopulate more rapidly.
This hybrid regimen incorporates features of both accelerated fractionation and hyperfractionation.
Two-dimensional (2D) radiotherapy consisted of a single beamfrom one to four directions. Beam set ups were usually quite simpleconsisting of opposed lateral fields or four field “boxes”.
With 3D-CRT, sophisticated computer programming is used todetermine the optimal beam shape and field arrangement. In addition, the multileaf collimator allows for the collimation of theX-ray beam during treatment.
- Advanced form of conformal radiotherapy.
- With this method, the radiation oncologistprescribes the treatment dose for a target volume and defines theallowable doses that surrounding normal structures can tolerate.
- The computer then performs repeated iterations to optimize beamintensity profiles and desired dose distributions.
IMRT differs from 3D-CRT; in that each X-ray beam is broken up into many “beamlets”, and the intensity of each beamlet can be adjusted individually. Hence, each field may have one or more areas of highintensity radiation and any number of lower intensity radiations, thusallowing for greater control of dose distribution with the target.
- Protons have a finite range likeelectrons but at the end of their range, the Bragg peak occurs,where they deliver maximum dose.
- By appropriately adjusting theproton beam, Bragg peak can be positioned within tumor almostanywhere in body, sparing normal tissues both proximal and distalto tumor.
- It is a specialized form of external beam radiation therapy.
- A particle accelerator accelerates protons, which are deflected by magnet to a target, which creates the neutron beam.
- Cancer cells that arehypoxic or that are in certain stages of the cell cycle or that areproficient at repairing damage are relatively resistant to being killedby photon or electron beam irradiation.
- Indicated in treatment of inoperable, unresectable or recurrent salivary glandtumors.
Because of the high biological effectiveness, a full course ofneutron therapy is delivered in only 10 to 12 treatments, comparedto 30 to 40 treatments needed for photons and electron irradiation.
- It causes more normal tissue damage than photon therapy.
- There is clinical difficulty in generating neutron particles.
- It combines two types of therapies—radiation therapy and immune therapy using monoclonal antibodies.
- Monoclonal antibodies are immune proteins made in the laboratory to target and attach to a special part (an antigen) of the surface of a cell.
- In radio-immunotherapy radiation-emitting molecules (radioisotopes) are attached to the tumor-specific monoclonal antibodies, which are injected into the body and they actively seek out the cancer cells and destroy themby the cytotoxic action of radiation.
- Therapy can be completed quickly, usually in one or twotreatments.
- It can minimize the risk of radiation damage to healthy cells.
- It may be complicated by anaphylactic reactions during andfollowing infusions.
- A single large dose of radiation is delivered in the operating suiteafter the tumor bed and adjacent normal organs have been defined.
- IORT typically involves the administration of electrons rather thanphotons.
- With electrons, the dose of radiation falls off rapidlywith depth, and the physician is thus able to spare normalunderlying tissues.
- The typical dose of IORT is 12 to 20 Gy in a single delivery.
- It provides the precise delivery of a single large dose of radiationto a target that typically measures less than 3.5 cm in diameter.
- The procedure can be administered by a linear accelerator, gammaknife or cyclotron.
- Stereotactic radiosurgery is used to treat skull base tumors andnasopharyngeal carcinomas.
Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness.
- Nitroxides (tempol).
- Other anti-oxidants (glutathione, lipoic acid, vit A, C and E,superoxide dismutase).
- Cysteine and Cysteamine.
- Novel radioprotectors (tetracyclines and fluoroquinolones).
- Radiosensitizers are agents that sensitize the tumor cells toradiation.
- These compounds apparently promote fixationof the free radicals produced by radiation damage at themolecular level.
- The mechanism of action is similar tothe oxygen effect, in which biochemical reactions in thedamaged molecules prevent repair of the cellular radiationdamage.
- Hyperbaric oxygen.
- Metronidazole and its analogs (misonidazole, etanidazole,nimorazole).
- Hypoxic cell cytotoxic agents (Mitomycin-C, Tirapazamine).
- Membrane active agents (procaine, lidocaine, chlorpromazine).
- Radiosensitizing nucleosides (5-Fluorouracil, Fluorodeoxyuridine, Bromodeoxyuridine, Iododeoxyuridine, Hydroxyurea, Gemcitabine, Fludarabine)
- Texaphyrins (motexafi n gadolinium).
- Supressors of sulfhydral groups (N- Ethylmalemide, Diamide andDiethylmaleate).
- Novel radiosensitizers (paclitaxel, docetaxel, irinotecan).
- Radiation-induced late normal tissue toxicity events include ongoing mitotic celldeath and perpetually active cytokine cascades that canlead to vascular damage, tissue hypoxia, and excessiveextracellular matrix deposition.
- Radiation mitigators aim to interrupt these cascades or intervene to prevent theperpetuation of damage and thus reduce the expressionof toxicity.
- Radiation mitigators can be agents deliveredduring or shortly after exposure to repopulate a critical cellcompartment such as the mucosa or bone marrow to prevent acute toxicity.
- Keratinocyte growth factor.
- ACE inhibitors (Captopril, Enalapril, ramipril).
- COX-2 inhibitors/NSAIDS (celecoxib, aspirin, ibuprofen).
- TGF= Tumor growth factor, ACF=Angiotensin converting enzyme.
- NSAIDS=Nonsteroidal anti-inflammatory drugs, COX- 2=Cyclo-oxygenase 2.
- Targeted therapies block the spread or growth of cancer by interfering with specific molecules or pathways involved in the growth and progression of cancer.
- The target molecule may be present in normal tissue, but is overexpressed or mutated in the cancer. These drugs can be more effective than cytotoxic chemotherapy as they are specific to the cancer.
- Targeted therapies do not damage normal cells in the way cytotoxic chemotherapy does.
- Targeted therapies can also be used in combination with chemotherapy and radiation therapy, and synergistic toxicities such as diarrhea and skin effects can occur.
- Small-molecule inhibitors are given orally.
- Small-molecule inhibitors are able to cross the cell plasma membrane and interfere with intracellular targets. They often act on multiple pathways in the cell.
- Protein kinases play an important role in regulating cellular activity and are often found to be mutated in cancer.
- Itblocks kinase activity and hence block cell growth.
1. BCR-ABL inhibitors: It blocks the BCR-ABL protein kinase which results from a chromosomal translocation (the Philadelphia chromosome) in chronic myeloid leukaemia.
• BCR = breakpoint cluster region, ABL = abelson murine leukemia oncogene-1 (BCR-ABL is a fusion gene created by the ABL1 gene on chromosome 9 to the BCR gene on chromosome 22)
2. Epidermal growth factor receptor inhibitors: EGFR tyrosine kinase inhibitors, such as erlotinib and gefitinib, act on the EGFR tyrosine kinase domain. Used to treat advanced non-small cell lung cancers that have the EGFR mutation
3. BRAF and MEK inhibitors: BRAF= Intracellular protein kinase that forms part of the mitogen-activated protein (MAP) kinase pathway and drives cell proliferation.
• Dabrafenib inhibits the activity of BRAF, an intracellular protein kinase of the RAF kinase family that drives cell proliferation and can be mutated in melanoma cells
• MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2.
• Trametinib inhibits the MEK pathway and has been combined with dabrafenib in an effort to reduce resistance to dabrafenib, and to reduce some of the adverse effects associated with BRAF inhibition.
4. Multi-targeted drugs including vascular endothelial growth factor inhibitors Sunitinib, sorafenib and pazopanib are kinase inhibitors that affect multiple pathways involved in cancer cell growth. In addition to blocking tyrosine kinase pathways they block the vascular endothelial growth factor (VEGF) protein which promotes angiogenesis.
Pain in cancer may be classified as:
- Pain due to tumor
- Loss of epithelial barrier; ulceration; exposure of nerves.
- Tumor necrosis; secondary infection.
- Chemosensitization of nerves; pressure on nerves.
- Tumor infiltration of bone, muscle, nerve, blood vessels.
- Exacerbation of dental or periodontal disease.
- Pain due to cancer therapy
- Pain following surgery.
- Acute surgical injury.
- Secondary infection.
- Myofascial or musculoskeletal syndromes.
- Neuroma; deafferentation pain.
- Pain due to radiotherapy
- Necrosis of soft tissue or bone.
- Myofascial or musculoskeletal syndromes.
- Exacerbation of dental or periodontal disease.
- Pain due to chemotherapy
- Peripheral neuropathy.
- Exacerbation of dental or periodontal disease.
- Pain unrelated to cancer or cancer therapy.
- Dental and periodontal pain controlled with analgesics and antibiotics along with definitivedental management.
- Management of mucositis.
- Bacterial, fungal, and viral infections are managed with specific antimicrobial agents.
- Neurologic pain like neuropathic pain and neuralgia-like pain require:
- Amitriptyline HCl with approx. daily adult dose of 10-100mg.
- Doxepin HCl with approx. daily adult dose of 10-100mg.
- Carbamazepine: 200-1,600 mg.
- Phenytoin: 200-600mg.
- Gabapentin 300-900mg.
- Treat the osteoradionecrosis.
- Chronic pain managed by counseling, relaxationtherapy, imagery, biofeedback, hypnosis, and transcutaneousnerve stimulation.
Abnormal speech, mastication and deglutition following surgery or radiation is due to:
- These conditionsaffects tongue mobility, mandibular movement, and soft-palate function.
- Changes in the patient’s perceptions of taste and smell due to radiotherapy.
- Taste may be affected directly due to an effect on the taste buds, or indirectly, due to hyposalivation and secondary infections.
- Total fractionated dose of >3,000 Gy reduces the acuity of all tastes (ie, sweet, sour, bitter, and salty).
- Taste usually recovers slowly over several months.
- Zinc supplementation (zinc sulfate, 220 mg twice daily) may be useful.
Musculoskeletal syndromes may arise after radiation and surgery due to:
- Fibrosis of muscles.
- Radiation exposure of the upper head of lateral pterygoid muscle.
- Emotional stress.
Mandibular stretching exercises and prosthetic aids may helpful.
- Occlusal stabilization appliances.
- Trigger point injections.
- Muscle relaxants.
- Tricyclic medications.
Effect on dentition:
- Agenesis of teeth.
- Agenesis of roots.
- Abnormal root forms.
- Abnormal calcification.
- Teeth may erupt even without root formation.
- Retained teeth for years.
Effect on facial skeleton:
- Altered growth of the maxilla.
- Asymmetric growth.
- Altered growth and development if treatment affects the pituitary gland.
ORN that affects the jaws is based on clinical presentation and observation: irradiated bone becomes devitalized and exposed through the overlying skin or mucosa without healing for 3 months, without recurrence of the tumour.
The Notani classification, is quickly applicable to all cases of mandibular osteoradionecrosis (ORN) after clinical examination and orthopantogram:
ORN confined to dentoalveolar bone
ORN limited to dentoalveolar bone or mandible above
the inferior dental canal, or both
ORN involving the mandible below the inferior dental
canal, or pathological fracture, or skin fistula
Epstein et al. classification of osteoradionecrosis
(A) No pathologic fracture
(B) Pathological fracture
Chronic persistent (nonprogressive)
(A) No pathologic fracture
(B) Pathological fracture
(A) No pathologic fracture
(B) Pathological fracture
Lyons et al. classification of osteoradionecrosis
<2.5 cm length of bone affected (damaged or exposed); asymptomatic. Medical treatment only.
>2.5 cm length of bone; asymptomatic, including pathological fracture or involvement of inferior dental nerve or both. Medicaltreatment only unless there is dental sepsis or obviously loose, necrotic bone.
>2.5 cm length of bone; symptomatic, but with no other features despite medical treatment. Consider debridement of loose or necroticbone, and local pedicled flap.
2.5 cm length of bone; pathological fracture, involvement of inferior dental nerve, or orocutaneous fistula, or a combination.
Reconstruction with free flap if patient’s overall condition allows
- Primary site of tumor.
- Posterior mandible is more commonly affected by ORN because of its compact and dense nature.
- Proximity of tumor to bone.
- Extent of mandible included in primary radiation field.
- State of dentition—odontogenic and periodontal disease.
- Poor oral hygiene.
- Radiation dose>60 Gy.
- Use of brachytherapy.
- Nutritional status.
- Concomitant chemo-radiation.
- Ill-fitting tissue borne prosthesis resulting in chronic trauma.
- Acute trauma from surgical procedures to the jaw.
- Advanced stage tumors.
- ORN affects the small blood vessels of bone, inducing inflammation (endarteritis), which favors the generation of small thrombi that obliterate the vascular lumen and thus interrupt tissue
- Radiation therapy produces an increase in free radicals and alters collagen synthesis.
- The bone loses its normal cellularity and undergoes fibrosisatrophy with impairment of its repair and remodeling capacity.
- Under such conditions even minimal external trauma causes ulceration, facilitating contamination and infection and thus favoring bone necrosis.
- Mandible more commonly affected than maxilla due to:
- Maxilla rich vascular supply.
- Absence of dense cortical plates in maxilla.
- Most lesions are perimandibular.
- Posterior mandible affected more readily than anterior because posterior part of mandible is more frequently in the direct field of radiation.
- Initially: Trismus, fetid breath, increased temperature.
- Discomfort or tendernessat the site.
- Bad taste.
- Paresthesia and anesthesia.
- Loss of mucosal covering and exposure of bone.
- Exposed bone is gray to yellow in colour.
- Exposed bone has a rough surface texture that abrades the adjacent soft tissues and causes further discomfort.
- Necrosis of exposed bone.
- Tissues surrounding the exposed bone may be indurated and ulcerated from infections or recurrent tumors.
- Formation of sequestra.
- Intense pain with intermittent swelling and drainage extraorally.
Pre- irradiation dental care:
- The non-restorable teeth should be extracted atraumatically under antibiotic coverage.
- Sufficient time to be given for proper healing 7-14 days.
- Judicious alveoloplasty to be done to permit linear closure of mucoperiostium.
- All sharp bony margins to be contoured because the irradiated bone does not remodel spontaneously.
- All restorable teeth to be restored.
- Periodontal therapy to be completed within this 2 weeks interval.
- Oral hygiene maintenance instructions.
- Application of fluoride in custom made trays:
- 4% Stannous fluoride gel.
- 1% sodium fluoride gel.
- 1% acidulated fluorophosphate gel.
Post- irradiation dental care:
- Denture not to be used in irradiated arch for 1 year after radiotherapy.
- Saliva substitute to lubricate the mouth because of decrease flow from irradiated mucous and salivary gland.
- Pilocarpine used to stimulate flow if residual salivary gland function present.
- If pulpitis develops, endodontic therapy to be started, care taken during instrumentation.
- Necessary extraction, limited to 1 or 2 teeth per appointment.
When ORN develops:
- Avoid mucosal irritants.
- Discontinue the use of dental appliances.
- Maintain nutritional status.
- Stop smoking and alcohol consumption.
- Topical antibiotic (tetracycline) and Antiseptic (chlorhexidine) rinses may reduce the potential local irritationfrom the microbial flora.
For chronic persisting ORN:
Local wound care:
- Penicillin V 500 mg QID X 7 days with
- Metronidazole 400 mg QIDX 7 days.
- Clindamycin 300 mg TID X 7days.
- Topical tetracycline rinses.
- Antiseptic mouthwashes (Chlorhexidine).
- Hyperbaric oxygen if needed.
For active progressive ORN:
- Appropriate analgesia should beprovided.
- HBO (hyperbaric oxygen)therapy: 20 to 30dives at 100% oxygen and 2 to 2.5 atmospheres of pressure for 90 minute sessions, five times a week followed by additional 10 dives.
- Sequestra managed by resectioning of the segment of involved bone to prevent occurrence of radiation compromised skin.
- Mandible reconstructed to provide continuity for esthetic and function.
- Non thermal effects used in the stimulation of tissue regeneration, healing of varicose ulcers, pressure sores, blood flow inchronically ischemic muscles, protein synthesis in fibroblasts,and tendon repair.
- Non thermal effects can result in healing of mandibular osteoradionecrosis.
- It is the oxygen under increased tension.
- HBO therapy consist of breathing 100% oxygen through a face mask or hood in a monoplace or a large chamber at 2.4 absolute atmospheric pressure for 90 minutes sessions(dive) for as many as 5 days a week totaling 30 or more sessions often followed by 10 additional dives, post surgically.
- Increased arterial and venous oxygen tension. The additional O2 is carried in physical solution in the plasma.
- O2 at high tension enhances the healing by a direct bacteriostatic effect on the microorganisms that renders them susceptible to lower antibiotic concentrations and also enhancing the phagocytic killing.
- Fibroblastic proliferation
- Collagen synthesis.
- Proliferation of granulation tissues increases and advances from increased O2 tension from the nondiseased periphery into the necrotic bone.
- As resorption and replacement of devitalized bone with healthy tissue progress, formation of sequestra that may undergo resorption is enhanced.
- When surgery is required after radiotherapy.
- When patient is at high risk due to high dose radiation to the bone with a high biologic effect (Time-Dose Fraction>109).
- When extensive surgery is required.
- Limited facilities.
- O2 Toxicity
- High pressure nervous syndrome.
- Decompression sickness.
- Arterial gas embolism.
- Tooth and sinus pain.
- Visual change.
- Gastric distress.
- Optic neuritis.
- It is a major limiting acute side effect of radiotherapy for head and neck cancer.
- OM may also occur with chemotherapeutic agents like 5-flurouracil (5FU) and methotrexate.
- Radiotherapy being a local treatment leads to mucositis in the irradiated area.
- Chemotherapy adds to the local mucositis as well as entire mucosa of the body.
Major steps in development and resolution of OM are:
- Initiation phase: DNA strand breaks and get damaged.
- Message generation phase: Activation of transcription factors /increased production of pro-inflammatory cytokines like interleukin (IL)-1β and IL-6.
- Signaling and amplification phase: Tumor necrosis factor alpha activates ceramide and caspase pathways.
- Ulceration phase: Breach in the mucosa, secondary bacterial and fungal infections.
- Healing phase: Cells regenerate and normal microbial flora is established.
Radiation Therapy Oncology Group (RTOG) and World Health Organization (WHO) have graded the severity of oral mucositis:
Grade I: Includes mucositis causing mild pain or congestion and require no analgesics.
Grade II: Includes development of patchy mucositis or those requiring analgesics and those producing sero-sanguineous discharge.
Grade III: Includes the development of confluent mucositis or severe pain that requires narcotic analgesics.
Grade IV: Involves the development of ulcer, necrosis or bleeding from the area.
- Grade I: Erythema which starts by the end of second week, followed by focal areas of desquamation.
- Grade II: Develops during the third week of RT, which then progresses to confluent mucositis.
- Grade III: Develops by fourth to fifth week and it warrants stoppage of radiotherapy asfurther injury to the mucosa causes permanent injury to themucosa.
Grade I Mucositis generally asymptomatic or may show intolerance to spices or hot food. The development of further severe mucositis produces following symptoms:
- Burning type of pain.
- Secondary bacterial and fungal infection further aggravates the symptoms.
- Swallowing and speech abnormalities.
- Weight loss and morbidity.
- Neurocognitive alterations.
- Development of grade IV mucositis leads to ulceration, necrosis and sometimes bleeding.
- Clinical examination of tissue change and assessments of symptoms.
- Use of Oral Mucositis Assessment Scale (OMAS).
- Cell morphology and viability of exfoliated buccal cells: the viability of cells can be determined by the trypan blue dye exclusion test, and a shift from mature to immature cells in mucositis.
Treatment of oral mucositis
- Interruption of radiation and restart at the earliest.
- Modification of radiation plan/re-planning as required.
- Pain management.
- Local anesthetic-lignocaine.
- Topical rinse-including aspirin and doxepin.
- Treatment of coexisting infection/control of oral candidiasis.
- Bezydamine mouth gargle.
- GM-CSF 4 lg/kg/d subcutaneous.
- Low level laser therapy, k = 8 nm, dosage = 3.0 J/point, total dosage/session = 36–40 J, spot size= 1 cm2, 15–20 min/session, 5 sessions/week, non-contact method
Agents with definite benefit for prevention/treatment of radiation induced oral mucositis/level of evidence (should be used):
- Benzydamine mouthwash to prevent oral mucositis without concomitant chemotherapy (Level-I)
- Low level laser therapy (wavelength around 632.8 nm) to prevent oral mucositis in patients undergoing radiotherapy, without
- concomitant chemotherapy (Level-III)
- 2 % morphine mouthwash may be effective to treat pain due to oral mucositis (Level-III)
Agents with doubtful benefit for prevention/treatment of radiation induced oral mucositis/level of evidence (may be used):
- Chlorhexidine mouthwash for prevention of OM (Level-III)
- Misoprostol mouthwash for prevention of OM (Level-III)
- Oral pilocarpine for prevention of OM (Level-III)
- Palifermin-keratinocyte growth factor (Level-III)
- Systemic zinc supplements administered orally may be of benefit to prevent oral mucositis (Level-III)
- L-glutamine for prevention of OM (Level-III).
- Bilateral exposure of the major salivary glands results in xerostomia.
- Radiation doses greater than a total dose of 3,000 cGy are at risk if all major glands are in the field.
- Irreversible effects occur at a total dose of 6,000 Gy for 5 weeks.
Effects of Radiation on salivary glands are:
- Acinar cell atrophy and necrosis.
- Changes in the vascular connective tissue.
- Altered neurologic function.
- Serous acini are affected earlier than the mucinous acini.
- Thick viscous secretion.
- Saliva production rapidly decreases and can be reduced by 50% after 1 week of standard fractionated radiation.
- Sialagogues after determination of salivary flow rates:
- Pilocarpine: Para sympathomimetic agent and has its major effects at the muscarinic cholinergic receptor of salivary gland acinar cells. Doses of up to 15 mg/d, increased secretion of saliva (cardiovascular side effects).
- Anetholetrithione: Increase the number of cell surface receptors on salivary acinar cells.
- Bethanechol: Stimulates the parasympathetic nervous system (75 to 200 mg/d in divided doses).
- If nosaliva is collected under resting or stimulated conditions, systemic agent will be effective.
- Use of sugarlessgum or candies.
- Caries associated with hyposalivation.
- Hyposalivation results in:
- Loss of remineralizing potential.
- Loss of buffering capacity.
- Increased acidity.
- Change in the bacterial flora(elevated Streptococcus mutans and Lactobacillus)
- Thick /copious saliva.
Three types of radiation caries:
- First type occurs as widespread superficial lesions attacking buccal, occlusal, incisal, and palatal surfaces.
- Second type involves primarily the cementum and dentin in the cervical region. These lesions mayprogress around the teeth circumferentially and resultin loss of the crown.
- Third type appears as a dark pigmentation of the entire crown. The incisal edges maybe markedly worn.
Some patients develop combinations of all these lesions.
- Daily application for 5 minutes of a viscous topical 1 % neutral sodium fluoride gel in custom-made applicator trays.
- Avoidance of dietary sucrose.
- Restorative dental procedures.
- Excellent oral hygiene.
1. Lingen MW, Kalmar JR, Karrison T and Speight PM. Critical evaluation of diagnostic aids for the detection of oral cancer. Oral Oncol 2008; 44: 10-22.
2. Kumar M, Nanavati R, Modi TG, Dobariya. Oral cancer: Eetiologic and risk factors: A review Journal of Cancer Research and Therapeutics 2016;12:458-63
3. Ram H, Sarkar J, Kumar H, Konwar R, Bhatt MLB • Mohammad S Oral Cancer: Risk Factors and Molecular Pathogenesis J. Maxillofac. Oral Surg 2011;10:132–137.
4. Corso G D, Villa A, Tarsitano A, Gohel A Current trends in oral cancer: A review Cancer Cell & Microenvironment 2016; 3: e1332. doi: 10.14800/ccm.1332;
5. Adam J. Kimple, Chris M. Welch, Jose P. Zevallos, Samip N. Patel Oral Cavity Squamous Cell Carcinoma – An Overview OHDM 2014;13:877-82.
6. Greenberg MS, Glick M. Oral Cancer. Burket’s Oral medicine diagnosis and treatment 10th edition published by Hamilton, Ontario. BC Decker Inc; 2003;194-234.
7. Speight PM. Update on Oral Epithelial Dysplasia and Progression to Cancer Head Neck Pathol. 2007;1: 61–66.
8. Nair D R, Pruthy R, Pawar U, Chaturvedi P Oral cancer: Premalignant conditions and screening – an update Journal of Cancer Research and Therapeutics – Supplement 2012;8:57-66.
9. Rajendran R, Sivapathasundharam Benign and Malignant Tumors of the Oral Cavity. Shafer’s Textbook of Oral Pathology, 7th edition Published by Elsevier, a division of Reed Elsevier India Private Limited 2012;104-30.
10. Shirani S, Kargahi N, Razavi SM, Homayoni S, Epithelial Dysplasia in Oral Cavity Iran J Med Sci. 2014;39: 406–417.
11. White SC, Pharaoh MJ. Malignant diseases of jaw Oral Radiology Principles and Interpretation 5th edition published by Mosby.2000; 458-80.
12. Mehrotra R, Gupta DK Exciting new advances in oral cancer diagnosis: avenues to early detectionHead & Neck Oncology 2011; 3:33.
13. Pałasz P, Adamski L, Chrząstek MG, Starzyńska A, Studniarek M. Contemporary Diagnostic Imaging of Oral Squamous Cell Carcinoma – A Review of Literature. Pol J Radiol, 2017; 82: 193-202
14. Decarlo K, Emley A, Dadzie OE, Mahalingam M. Laser capture microdissection: methods and applications. Methods Mol Biol. 2011;755:1-15.
15. American Cancer Society. Treating Oral Cavity and Oropharyngeal Cancer. available from https://www.cancer.org/content /dam/CRC/ PDF/Public / 87 66.00.pdf.
16. Kasat V, Sahuji S, Joshi M. Radiotherapy: An Update. Journal of Indian Academy of Oral Medicine and Radiology2010;22:26-30.
17. Raviraj J, Bokkasam VK, Kumar VS, Reddy US, Suman V. Radiosensitizers, radioprotectors, and radiation mitigators. Indian J Dent Res 2014;25:83-90.
18. Khalighi M. Pain Management. Available from: https://depts.washington. edu/uwmedres/pdf/ hospitalist/Pain_Management.pdf.
19. Carrington C. Oral targeted therapy for cancer Aust Prescr. 2015;38: 171–176.
20. Nadella KR, Kodali RM, Guttikonda LK, Jonnalagadda A Osteoradionecrosis of the Jaws: Clinico-Therapeutic Management: A Literature Review and Update J. Maxillofac. Oral Surg 2015;14:891–901.
21. Rathy R, Sunil S, Nivia M Osteoradionecrosis of mandible: Case report with review of literature Contemporary Clinical Dentistry.2013;4:251-53.
22. Mallick S, Benson R, Rath GK Radiation induced oral mucositis: a review of current literature on prevention and management Eur Arch Otorhinolaryngol 2016; 273:2285-93.