Epidemiology of oral cancer. Precancerous lesions and conditions, primary prevention and surgical management

1: Epidemiology of oral cancer

Oral cancer: world scenario

Oral cancer is one of the ten leading cancers in the world. Globally the age adjusted incidence rates for oral cancer in men varies from 2.2/100000 in Japan to 22.5/100000 in Brazil; and in women from 0.9/100000 in Japan to 17.2/100000 in Bangalore. In south East Asia, it is the leading cancer in males and the third leading cancer in females. For description the following subsites are included in oral cancers: lip.tongue,gum, floor of mouth, buccal mucosa palate and other parts of the mouth (ICD-0140,141,143,144,145)

There is considerable international, national, interethnic variation in the distribution of cancer in intraoral sites. Cancer of the buccal mucosa, lower alveolus and the retro molar trigone are grouped together as cancers of gingivo buccal complex and can be aptly called as the Indian oral cancer as they constitute 60% of all oral cancer in India. Tongue and floor of mouth cancers form the bulk of oral cancers in the west.

Magnitude of cancer in India:

Until the National Cancer Registry Program became active nationwide information was not available for incidence of cancer in India .the Indian council of medical research sponsored cancer registries under the National Cancer Registry Program (NCRP) in 1981 to provide reliable data on cancer in India. There are hospital based registries and population based registries

Cancer has emerged as a major chronic disease in India and it is estimated that over 700000 develop cancer every year. The NCRP data on the incidence rates of cancer from the various registries are shown in table no: 1 a and b. the incidence of cancer in India is compared to the incidence of some leading registries in the world in table no 2.

Oral cancer in India:

Magnitude of the problem.

The NCRP in its 1987 report has estimated that there could have been 61,500 oral cancers in India in 1990; and by turn of the century, this figure will go up to 77,000 cases. In 2011 over 95,000 Indians will develop oral cancer. At any given time there will be more than double the number of incident cases of oral cancer in the community. Thus it can be expected that there will be 2,00,000 oral cancers India as of today.

There is marked variation in the incidence of cancers of various regions of oral cavity from registry in India as shown in table nos: 3A &B and4 A & B.

Time trends

There is no significant difference I the time trends of oral cancer except that there is a reduction in the cancer of buccal mucosa in some of the registries.

Natural history:

In the long period between initiation and development of invasive oral cancers, well defined oral precancerous lesions/conditions occur. The commonest of these are leukoplakia, erythroplakia and oral submucus fibrosis. The prevalence of leukoplakia in the general population ranges from 0.7% to 5%.the mean age distribution of persons wit preleukoplakia was found to be 43.5 years , leukoplakia 45.6 years and oral cancer 57.6 years in a recent study from Trivandrum.

Malignant transformation of leukoplakia was not observed in age groups of less than 35 years; whereas it was 3.5 times higher in the age group 55years and above when compared to that of age group 35- 54 years. The erosive (ulcerated) speckled (nodular) and verrucous type are rated as high risk type and homogenous type as low risk type. Erythroplakia show carcinoma and dysplasia 17 times more frequently than leukoplakias. This information can be effectively utilized in formulation of screening programmes for oral cancer.

ORAL CANCER CONTROL

It is clear that the use of tobacco in any form is casually associated with oral cancer. The primary prevention of oral cancer is most cost effective. Out of a possible 95000 oral cancers in India in one year, over two thirds could have been avoided. The best strategy for control of cancer is tobacco behavior modification.

This has been successfully demonstrated in the west for lung cancer. After the launching of the National Cancer Control Programme in 1984 various groups in the country are addressing tobacco control activities to suit each region of the country and with utilization of limited finance

Chemoprevention is a new area in oral cancer control and refers to administration of natural substances and synthetic compounds for reducing cancer risk. Our group has extensive experience in chemoprevention of oral cancer with vitamin A (200,000 IU /weekly x 6 months) and beta-carotene (30 mg daily x 6 months). Once clinical remission is observed a low maintenance dose of vitamin A (50000 IU weekly) is adequate to maintain the protective effect.

A prescription type chemoprophylaxis is not practical in India, taking into consideration the large numbers and poor socio-economic status of the high risk group for oral cancer. Dietary modulation to consume plenty of green and yellow vegetables and fruits will be the practical approach to chemoprevention of oral cancer.

Secondary prevention of oral cancer is achieved by early detection and prompt treatment Kap surveys have shown that through cancer awareness is to be created in the community. Professionals also require updating regarding the approaches towards a cancer related physical examination and appropriate referrals. Our experience has shown that health workers and trained volunteers can be effectively used for early detection and surveillance of oral cancer in the villages. Mouth self examination is another technique found effective in early diagnosis of oral cancer in Kerala. However this method may be tested in areas where the literacy level is low.

The outcome measures as a result of the intervention process should be a reduction in the tobacco use and earlier stages of presentation of oral cancer in treatment centres. These could result in longer survival rate and reduction in the morbidity and mortality from this disease.

In conclusion,oral cancer induced by tobacco is among the few human cancers for which our understanding of etiology has reached a state to allow formulation of programmes aiming at reduction and ultimate elimination of morbidity from these cancers.

Table 1 (A)

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Table 1(b)

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Table 2

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Source National Cancer Registry Programme Data 1987

Table 3 (a)

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Table 3(b)

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Table 4(a)

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Table 4(b)

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REFERENCES

1. Parkin DM(Ed):cancer occurrence in developing countries. IARC scientific publication no75. International agency for research on cancer,Lyon France,1986.

2. Muir C,Waterhouse J,Mack,Tetal(Eds):cancer incidence in 5 continents. Vol5 IARC scientific publication no88,IARC,Lyon 1987

3. Mehta F S,Gupta P C and Pindborg J J:chewing and smoking habits in relation to precancers and oral cancer. J cancer Res Clin Oncol 1981:99:35-39

4. Mehta F S,Pindborg J J,Gupta P C et al. Epidemiologic and Histologic study of oral cancer and leukoplakia among 50915 villagers in India. Cancer 1969:24:32-39

5. Zachariah J,Babu Mathew,Varma NA R et al. Frequency of oral mucosal lesions among 5000 individuals in Trivandrum JAIDH 1966:38:290-296

6. Sankaranarayanan R:oral cancer in India,an epidemiologic review. Oral Surg Oral Med Oral Path 1990:325-330

7. Banoezy J.Clinical and histological aspects of oral premalignant lesions. In oral oncology Boston,Wanderwall and Snow G B(Eds). Martinus Wigholf Publishers- Boston 1984:3-31

8. Bhandkamar S M. Action on control of tobacco. Role of state government. Tobacco and health:the Indian Scene. Sanghvi L D and Notani P(Eds) UICC Workshop,Bombay 1989:188-92

9. Babu Mathew.Action on Tobacco Control: Role of National service scheme:Tobacco and Health;The Indian Scene.Sanghvi LD, and Notani P(Eds) UICC Workshop,Bombay1989,202-204

10. Bhargava MK, Godwa L J, Ramakrisna V etal. Development of interventional studies in Karnataka to modify tobacco related behaviour. Tobacco and Health: The Indian Scene. Sanghvi LD and Notani P (Eds) UICC.Workshop, Bombay 1989:150-158

11. Vaidya Gand Nayik U B. Action on Tobacco control. The role of school children. Tobacco and Health: The Indian Scene. Sanghvi LD and NotaniP (Eds) UICC. Workshop , Bombay 1989 :163-173.

12. Gupta P C, Mehta F S, Pindborg J J et al : Interventional study for primary prevention of oral cancer among 36,000 Indian Tobacco users. The Lancet 1986 :1:1235-1239

13. Babu Mathew, Shankaranarayanan R, Stich H F et al. Chemoprevention of oralprecancerous lesions in tobacco users. In chemoprevention of cancer, Bhide S V andMaru G B (Eds) Omega scientific publishers, New Delhi 1992 91-99

14. Babu Mathew,Ramany SW, Pai DK et al. Battle against Cancer at Chavassery. In Proceedings of Kerala Science Congress. Balakrishnan K (Ed) Trivandrum 1981. 418-420

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16. Shankaranarayanan R, Krishnan Nair.M , Babu Mathew et al. Recent results of oral Cancer research in Kerala, India. Head and Neck 1992 : 14:107-112

2. Primary prevention of oral cancer

The overall goal of cancer prevention and control is to reduce the incidence and mortality of cancer and to improve the quality of life of cancer patients and their families. [1] A well conceived national cancer control programme is the most effective instrument to bridge the gap between knowledge and practice and achieve this goal. Integrated into existing health systems and related services, these programmes ensure systematic and equitable implementation of control strategies across the continuum of prevention, early detection, treatment and palliative care, as set out in WHO guidelines

For national cancer control programmes. [2] A national cancer control programme can help policy-makers and programme managers make the most efficient use of available resources to benefit the whole population by taking a balanced approach to evidence based interventions. India has come out with the National Cancer Control Programme in 1984. Prevention frequently offers the most cost effective long-term strategy for cancer control. Furthermore, cancer preventive measures are beneficial as they can also contribute to preventing other chronic diseases that share the same risk factors.

Primary prevention is the most cost effective method to fight oral cancer. Primary prevention may be defined as the action taken prior to the onset of disease. It signifies the intervention in the prepathogenesis phase of the disease. It has been estimated that 65- 80% of oral cancer is environmental, attributable to lifestyle and thus may be prevented.[3] Based on reports in India, a third of all new cancer cases are related to tobacco. It is estimated that around 43% of cancer deaths are due to tobacco use, unhealthy diets, alcohol consumption, inactive lifestyles and infection. Of these, tobacco use is the world’s most avoidable cause of cancer. The consumption of alcohol and tobacco is closely associated not only with the development of OC, but also with the course of the disease and this consumption is associated with a poor prognosis. The lack of public awareness of the signs, symptoms and risk factors associated with oral cancer has been reported. Unfortunately, most oral therapeutic modalities, the prognosis of patients with oral malignancies has remained poor.[4]

There are three main strategies for primary prevention.

(1) Avoidance or reduction of risk factors.
(2) Chemoprevention
(3) Avoidance of genetic risk.

1. Avoidance of the risk factors

The various etiologic factors of oral cancer include

a.Tobacco. All forms of tobacco — cigarettes, pipes, cigars, and smokeless tobacco have been implicated in the development of OC[5] . While tobacco confers the highest risk for OC of the floor of the mouth also, it is associated with an increased risk for all sites of OC. Tobacco use is responsible for 90% of OC deaths in males[6].

b.Alcohol . Alcohol use is a second independent major risk factor for the development of OC. For non-smokers it is the most important risk factor. [7,8]. Above30 grams of alcohol per day, risk increases linearly with amount of alcohol consumed. [9].

c.Arecanut . In addition to tobacco use, the use of chewing products such as betel nuts, paan, chaalia, gutka, naswar, and areca increases the risk for OC; these products are socially acceptable in Southeast Asia, the South Pacific Islands, and India. [10]

d.Poor nutrition. The contribution of diet to cancer risk in developing countries has been considered to be lower, perhaps around 20%. Dietary deficiencies, particularly of vitamin A, vitamin C, vitamin E, iron, selenium, foliate and other trace elements have been linked to increased risk of OC. [11,12]. Overall, a high intake of fruits and vegetables probably reduces the risk of oral cancer, and consumption of very hot drinks and foods typically consumed in some cultures probably increases the risk of cancers of the oral cavity and pharynx

e.Actinic radiation . Solar irradiation is a major risk factor for cancer of the lip. The vast majority of lip cancer occur on the lower lip and many patients have outdoor occupations where sun exposure is increased. Lip cancer is three times more common in men than women which may be an effect of occupation, smoking and sun-exposure. [13]

f.Chronic irritation. It has been suggested that chronic irritation to the lining of the mouth from poorly fitting or defective complete dentures or sharp teeth may be a risk factor for OC. [14].

g.Dental plaque . Polymicrobial supragingival dental plaque is a possible independent risk factor, as it possesses a relevant mutagenic interaction with saliva, and thus oral health may be a co-factor in the development. [15] of OC.

h.Mouth rinses. Ethyl alcohol is added to mouth rinses as a solvent for other ingredients and as a preservative. Study shows that cancer was not statistically associated with mouthwash use in alcohol or tobacco users[16].. Currently, there is insufficient clinical evidence to suggest a relationship between ethyl alcohol found in mouth rinses and OC.

i.Candidiasis. Autoimmune polyendocrinopathycandidiasis- ectodermal dystrophy an autosomal recessive disease associated with a limited T lymphocyte defect, and exceptionally common in Finland, seems to favour the growth of Candida albicans. Candidial infection is associated with accanthosis and parakeratosis and predispose to chronic mucositis and OC. [17]

j.Diabetes. The molecular basis for the putative association of diabetes mellitus with oral squamous cell carcinomas (OSCC) from epidemiological studies, may involve insulin receptor substrate-1 and focal adhesion kinase[18] .

k.Free radicals. Free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) can function both as initiators and promoters in carcinogenesis, while antioxidants provide protection against the cellular and molecular damage caused by reactive oxygen species and reactive nitrogen species. [19] The increase in ROS and RNS may have been the event that led to the consumption and reduction of salivary antioxidant systems, thus explaining the oxidative damage to the DNA and proteins, and possibly the promotion of OC[20].

l.Viruses . The role of viruses remains unclear. Evidence is perhaps strongest for infection with high-risk human papilloma viruses (HPV) [21, 22]. Studies show an increased risk of OC in women with cervical cancer suggesting a common risk factor other than smoking, such as HPV infection: transmission of HPV via oral sex is one possibility. A recent multicentre case control study reported that infection with HPV-16 increased the risk of cancer of the oral cavity and particularly oropharynx. The role of infection with Epstein-Barr virus and herpes simplex viruses (HSV) remains uncertain. Heavy use of tobacco, alcohol and HPV-16 infection was associated with an increased risk of OSCC but, after adjusting for age, tobacco, alcohol use, and number of sexual partners, the risk of cancer was not significantly increased in those with HSV-1 or HSV-2, though seropositivity to HSV-1 and HSV-2, may modify the risk associated with exposure to tobacco, alcohol, or HPV.

m.Family History. Family history of OC is a risk factor. Head and neck cancer patients show an increased susceptibility to chromosome damage by mutagens[23]. Study used cDNA array and identified genes such as keratin 17 and 19, laminin-5, connexin-26 and vascular endothelial growth factor (VEGF) as being differentially expressed in head and neck SCC tissues, with respect to normal tissue[24].

n.Common oral premalignant lesions and conditions Leukoplakia, Erythroplakia Erythroleukoplakia, Traumatic ulcer, Palatal changes associated with reverse smoking Submucous fibrosis, Plummer- Vinson`s Syndrome, Syphilitic glossitis, Lichen Planus, Discoid lupus erthematosis, Diskeratosis congenita, ? Chelitis glandularis

The general dentists have ample opportunities in all these areas. The strategies for the control of habitual consumption of tobacco, arecanut and alcohol are (1) creation of awareness about their hazards, (ii) legislation to restrict the production and sale, (iii) advocacy activities to make their consumption an unaccepted social practice and (iv) establishment of habit cessation clinics. The General Dental practioner can act on all four areas. On an individual basis when an arecanut/tobacco/alcohol habitué is identified during oral examination, that person should be made aware about the hazards of the addiction and advised to stop tobacco and alcohol consumption. If needed, assistance may be given to quit the habit. The Dentist can function as a resource person in anti-tobacco activities organized by Non-Governmental Organisations and Community Groups like the Residents’ Association. Dentists should join hands with Governmental programmes for tobacco control. It is gratifying to note that the members of the Indian Dental Association are now collectively taking up oral cancer control and tobacco control activities. The general practitioners have an important role in early detection of premalignant lesions and conditions and their prompt treatment and follow ups thus preventing malignant transformation. American Cancer Society recommends examination for cancer of the oral region every 3 years for persons 21 years of age and older and annually for those 40 years of age and older. A first line of defence against oral cancer is an orofacial self-examination. The Dentist can play an important role in educating and motivating to perform self examination f the oral cavity. A self-examination can help individuals become more aware of their own bodies and involve them in monitoring their own health.

Chemoprevention

Chemoprevention is the process by which cancer is prevented or delayed from developing by the administration of simple substances to high risk groups. Chemoprevention is effective in oral cancer. Human clinical trials have shown that Vitamin A, Synthetic retinoids, caratinoids,Vitamin C, Vitamin E, Selenium, Spiruluna, Lycopin etc to have varying degrees of protective effects in oral cancer It is estimated that there are over 700 million high risk patients in the world now. As there is need for prolonged treatment, chemoprevention is expensive. Hence poor patients find it difficult to persue full course. Therefore, more than a prescription type of treatment, a proscription type of management banning tobacco/alcohol with dietary modulation to use daily green and yellow vegetables and fruits, will be a more feasible goal of chemoprevention for developing countries[24]. Dental surgeons are in very good position to offer chemoprevention advices to high risk groups

Genetic counselling.

Very few oral cancers have genetic predisposition and shows definite pattern of inheritance. Therefore genetic counseling has only a low role in primary prevention of oral cancer .

The Effective partnerships at national, regional and global levels are essential for sustainable prevention and control of cancer. Since the discontinuation of the Global Alliance on Cancer Control, WHO has strengthened its links with other institutions active in the field of cancer control by bringing together partners in a network whose in global cancer control, advocacy for such control, provision of a forum for communication and exchange of information and facilitation of implementation of cancer control programmes at country level. The network comprises international organizations, agencies of the United Nations system, government bodies, nongovernmental organizations, and private-sector entities, covering such fields of expertise as medicine, nursing, research, public health and communications.

REFERENCES

1. Poul Erik Petersen. Oral cancer prevention and control – The approach of the World Health Organization Oral Oncology.

2. World Health Organization. National cancer control programmes: policies and managerial guidelines: executive summary. Geneva: WHO, 2002.

3.Park`s textbook of preventive and social medicine, K Park, nineteenth edition.

4. Essentials of Preventive and Community Dentistry, Soben Peter 4th edition

5. Spitz MR, Newell GR. Descriptive epidemiology of squamous cell carcinoma of the upper aerodigestive tract. Cancer Bull 1987; 39: 79–81.

6. Cinciripini PM, McClure JB. Smoking cessation: recent developments in behavioral and pharmacologic interventions.Oncology (Williston Park) 1998; 12: 249–56.

7. Altieri A, Bosetti C, Gallus S, et al. Wine, beer and spirits and risk of oral and pharyngeal cancer: a case-control study from Italy and Switzerland. Oral Oncol 2004; 40: 904–9.

8. Franceschi S, Levi F, Dal Maso L, et al. Cessation of alcohol drinking and risk of cancer of the oral cavity and pharynx. Int J Cancer 2000; 85: 787–90.

9. Rodriguez T, Altieri A, Chatenoud L, et al. Risk factors for oral and pharyngeal cancer in young adults. Oral Oncol 2004; 40: 207–13.

10. Chen PC, Pan CC, Kuo C, Lin CP. Risk of oral nonmalignant lesions associated with human papillomavirus infection, betal quid chewing, and cigarette smoking in Taiwan: an integrated molecular and epidemiologic study. Arch Pathol Lab Med 2006; 130: 57–61.

11. Taghavi N, Yazdi I. Type of food and risk of oral cancer. Arch Iran Med 2007; 10: 227–32.

12. Pavia M, Pileggi C, Nobile CG, Angelillo IF. Association between fruit and vegetable consumption and oral cancer: a meta-analysis of observations studies. Am J Clinical Nutr 2006; 83: 1126–34.

13. Perea-Milla Lez E, Mirro-Del Moral RM, Mart 匤 ez-Garc 僘 C, et al. Lifestyles, environmental and phenotypic factors associated with lip cancer: a case-control study in southern Spain. Br J Cancer 2003; 88: 1702–7.

14. Rosenquist K, Wennerberg J, Schildt EB, et al. Oral status, oral infections and some lifestyle factors as risk factors for oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden. Acta Otolaryngol 2005; 125: 1327–36.

15. Bloching M, Reich W, Schubert J, et al. The influence of oral hygiene on salivary quality in the Ames Test, as a marker for genotoxic effects. Oral Oncol 2007; 43: 933–9.

16. Rautemaa R, Hietanen J, Niissalo S, et al. Oral and oesophageal squamous cell carcinoma-a complication or component of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I). Oral Oncol 2007; 43: 607–13. Experimental Oncology 30, 259–264, 2008 (December) 263

17. Goutzanis L, Vairaktaris E, Yapijakis C, et al. Diabetes may increase risk for oral cancer through the insulin receptor substrate-1 and focal adhesion kinase pathway. Oral Oncol 2007; 43: 165–73.

18. Rasheed MH, Beevi SS, Geetha A. Enhanced lipid peroxidation and nitric oxide products with deranged antioxidant status in patients with head and neck squamous cell carcinoma.

Oral Oncol 2007; 43: 333–8.

19. Bahar G, Feinmesser R, Shpitzer T, et al. Salivary analysis in oral cancer patients: DNA and protein oxidation, reactive nitrogen species, and antioxidant profile. Cancer 2007; 109: 54–9.

20. Herrero R, Castellsagu ・ X, Pawlita M, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003; 95: 1772–83.

21. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005; 14: 467–75.

22. Spitz MR, Fueger JJ, Beddingfield NA, et al. Chromosome sensitivity to bleomycin induced mutagenesis an independent risk factor for upper aerodigestive tract cancer. Cancer Res 1989; 49: 4626–8.

23. Villaret DB, Wang T, Dillon D, et al. Identification of genes over expressed in head and neck squamous cell carcinoma using a combination of complementary DNA subtraction and microarray analysis. Laryngoscope 2000; 110: 374–81.

24. Babu Mathew, R Sankaranarayanan, H F Stitch, M K Nair. Chemoprevention of precancerous oral lesions in tobacco users. Chemoprevention of cancer. Eds S Bhide, Maru R. Published from TATA Memmorial hospital, Bombay. 1994 pg 91-97

3. Precancerous lesions & conditions

CONCEPT OF PRECANCER

Generally, an altered state of tissue often,but not always shows high potential to undergo malignant transformation. Some benign lesions or conditions,for a varying length of time, also precede oral cancer. The interesting thing is that these lesions and conditions share the same etiological factors with oral cancer,particularly the use of tobacco and exhibit same site and habit relationship. Many of them show high potential to become cancer and are therefore termed precancerous.

It is quintessential to remember that a premalignancy is not guaranteed to eventually transform into cancer as is erroneously believed. But an individual with oral pre-cancer is definitely at a 69 times greater risk of developing oral cancer as compared to tobacco users who do not have a pre-cancerous lesion.

Classification of oral pre-cancer:

- Pre-cancerous lesions-it is defined as a morphologically altered tissue in which cancer is more likely to occur than its apparently normal counterparts.
- Leukoplakia
- Erythroplakia
- Mucosal changes associated with smoking habits-Nicotina Palatini
Snuff Dipper’s lesion
Tobacco pouch keratosis
- Bowen disease
- Pre-cancerous conditions-it is defined as a generalised state or condition associated with significantly increased risk for cancer development.
- Oral submucous fibrosis(OSMF)
- Oral lichen planus
- Sideropenic dysphagia
- Dyskeratosis congenita
- Discoid Lupus Erythematosus
- Plummer Vincent syndrome
- Cheilitis Glandularis
- Central papillary atrophy of tongue
- Tertiary syphilis

PREMALIGNANT LESIONS

The term originates from 2 greek words- leuko i.e. white and plakia i.e. patch.

Definition by WHO- it is a whitish plaque or patch that cannot be characterised, clinically or pathologically, as any other disease and which is not associated with any other physical or chemical causative agent except the use of tobacco.

Incidence and prevalence

Leukoplakia is by far the most common precancer, representing 85% of such lesions. Based on pooled,weighted data from previously reported studies,the worldwide prevalence of LP is estimated between 1.5%-4.3%. Thereis a strong male predilection(70%), except in regional populations in which women use tobacco products more than men. However a slight decrease in proportion of affected males has been noted over the past half century. The disease is diagnosed more frequently now than in the past,probably because of an enhanced awareness on the part of health professionals.

Clinical Classification of leukoplakia

According to clinical description

A)Homogenous- a completely white lesion

- Flat- smooth surface
- Corrugated-like a beach at ebbing tide
- Pumice like-with a pattern of white lines(cristae)
- Wrinkled-like dry cracked mud surface.

1) Ulcerated- lesion exhibits red area at the periphery of which white patches are present.
2) Nodular or speckled- charactarised by white specks or nodules on erythematous base.
3) Verrucous-slow growing, papillary proliferations above the mucosal surface that may be heavily keratinised. Extensive lesion of this type is called ‘oral florid papillomatosis’.
4) Erythroleukoplakia-leukoplakia present in association with erythroplakia.

According to future risk of development of oral cancer

- High risk sites
- Floor of mouth
- Lateral or ventral surface of tongue
- Soft palate
- Low risk sites
- Dorsum of tongue
- Hard palate
- Intermediate group
- All other sites of oral mucosa

According to histology

- Dysplastic
- Non-dysplastic

According to extent

- Localized
- Diffuse

Clinical features

- Sex and age distribution: more common in older age group,i.e.35-45 years and above. Males are more frequently affected due to direct consequence of habit.
- Common sites: can occur anywhere in oral mucosa. Buccal mucosa and commissures are more commonly involved. Lip lesions more common in men and tongue lesions seen more in women. The involvement of various sites depends on type of habit. Sometimes in edentulous patient,alveolar ridge can be involved.
- Commissural LP: lesion extending posteriorly from labial commissure over a distance of 2cm, in triangular shape.

In buccal sides, it involves central zone of buccal mucosa in molar region and along occlusal line.

- Locations in descending order of frequency of involvement: commissures, buccal mucosa, lips, tongue,palate,alveolar ridge,floor of mouth,soft palate and gingival.
- Sublingual keratosis: LP occurring in floor of mouth and ventral surface of tongue.
- Ebbing tide type: LP in floor of mouth that appear similar to undulations left on the sand by the ebbing tide. It occurs due to loose binding and consequent movement of the mucosa in the floor of the mouth.
- Extent: extent of involvement may vary from small,well-localised, irregular patches to diffused lesions involving considerable portion of oral mucosa. Multiple areas of involvement are not uncommon.
- Color: lesion may be white or yellowish white, but with heavy use of tobacco,lesion may assume brownish color.
- Surface: often wrinkled or shrivelled and may feel rough on palpation.
- Symptoms: some patients may report a feeling of increased thickness of mucosa. Those with ulcerated and nodular type may complain of burning sensation. Enlarged cervical lympnnodes maysingnal occurrence of metastasis.

Clinical types

- Pre-leukoplakia or mild or thin leuloplakia :it is alow grade or very mild reaction appearing as grayish white but not completely white lesion with slight lobular pattern. Their margin can be well demarcated or it blends with adjacent mucosa.these lesions are soft, translucent and thin.
- Homogenous or thick leukoplakia: also called leukoplakia simplex. It accounts for 84% of cases. LP seen amongst clay pipe smokers and betel quid chewers are generally of homogenous type. They have no red component.
- Appearance:usually localised lesions of extensive white patches present a relatively consistent pattern throughout. Sometimes it may be corrugated, with pattern of fine lines or wrinkled or papillomatous surface.
- Size and margin: characterised by raised plaque formation consisting of single or group of plaques with irregular edges.
- Color: usually white but can be yellowish white or yellow.
- Ulcerated leukoplakia: occurs in 13% cases.
- Appearance:Characterised by red area which at times exhibit yellowish areas of fibrin,giving the appearance of ulceration.
- Periphery: White patches found at periphery of lesion. Sometimes associated with pigmentations on periphery.
- Sites:seen exclusively at commissures and anterior part of buccal mucosa.
- Nodular leukoplakia: also called ‘speckled LP’ or ‘leukoplakia erosiva’.
- Appearance:It is a mixed red-white in which small keratotic nodules are scattered over an atrophic patch of oral mucosa.
- Size: Nodules may be pinhead sized or even larger.
- It has got a high malignant potential.
- Verrucous leukoplakia:also called ‘ leukoplakia verrucosa’.
- It is characterised by verrucous proliferation over mucosal surface. These lesions demonstrate sharp and blunt projection which are heavily keratinised.
- Sites:buccal mucosa,alveolar mucosa,tongue,floor of mouth,gingival,lips.
- Appearance:white lesion with a broken up surface due to multiple papillary projections that may be heavily keratinised. They may be accompanied by homogenous LP on other mucosal surfaces.
- Proliferative verrucous leukoplakia(PVL): verrucous LP can become more exophytic with development of multiple keratotic plaques with roughened surface projection. PVL has got strong female predilection and is present in patient who don’t use tobacco. It can spread and involve adjacent mucosa. As the disese progresses it transforms into a lesion that is clinically and microscopically identical o verrucous carcinoma or squamous cell carcinoma.
- Erythroleukoplakia: in some lesions of LP red component is present . this intermixed lesion is called erythroleukoplakia.

Malignant potential

- Malignant transformation occurs in 0.3%-10% of cases.
- It is higher in women(6%) than men(3.9%) due to involvement of endogenous factors.
- LP associated with chewable tobacco shows higher rate of malignant transformation.
- Buccal mucosa and commissure-1.8%
- Lip and tongue =16%-38.8%
- Nodular dysplasia has higher risk of malignant transformation than other clinical types.
- Idiopatic LP and candida associated LP also come under high risk group.
- High risk factors
- Persistence of lesion for many years
- Female patient
- Lesion situated on margins,base of tongue and floor of mouth.
- Erosive lesions
- Combination of above factors.

Prognosis

Prognosis is quite fair. rate of regression is higher when tobacco habit is discontinued.

Management

- Elimination of etiological factors
- Prohibition of smoking
- Removal of chronic irritant like sharp,broken teeth.
- Elimination of other etiological factors like syphilis,alcohol,dissimilar metal restoration,etc
- Conservative treatment
- Vitamin therapy: it has a protective effect on epithelium.

Daily requirement=4000IU. It is given orally,parentrally or topically.

Therapeutic dose=75000-300000IU for 3 months.

Vit A may be used topically after painting the lesion with podophyllin solution(it inhibits mitosis)

- Vit A +Vit E: to inhibit metabolic degradation.
- 13-cis-retinoic acid: synthetic analogue of vit|A; given in high doses of 1.5-2mg/kg body wt for 3 months. If relapse occurs then low doses of 0.5mg/kg are given for 9 months.
- Antioxidant therapy: beta-carotene supplementation can be beneficial for LP.
- Vit A palmitate: short term treatment with vitA palmitate along with aromatic retinoid of all trans-B-A vitamin acid+B-cisB-A vitamin acid may show healing and improvement.
- Nystatin therapy:in candidal LP
- Vit B complex:supplement in commissural and lingual lesions
- Panthenol: panthenol lingual tablet and oral spray used against glossitis and glossodynia
- Surgical management
For proper treatment, biopsy is taken for microscopic examination. The most meaningful sites for taking biopsy specimen are the areas that display greater surface irregularities like fissures and cracks and erythematous areas.
- Conventional surgery
- Cryosurgery:cell death occurs at -20oc.
- Fulguration(electrocautery and electrosurgery)
- LASER

- Biopsy
- Laser peel-to remove the lesion that involves relatively large surface area.
- Ablation-method of painting away a lesion or tissue removed by a laser.

ERYTHROPLAKIA

It is also called Erythroplasia of Queyrat . it is a persistent red velvety patch. Reddish color results from absence of surfacekeratin layer and due to presence of connective tissue papillae containing enlarged capillaries projected close to the surface.

A chronic red macule which cannot be given any other specific diagnostic name and cannot be attributed to traumatic,vascular or inflammatory causes.

Speckled or granular

Erythroplakia interspersed with patches of LP.

- Idiopathic
- Alcohol
- Smoking
- A secondary infection or superinfection with candidiasis may be associated with dysplastic oral mucosal cells. It diminishes on antifungal therapy.

Clinical features

- Age and sex-male predilection and most common in 6th and 7th decade of life
- Sites-occurson all mucosal surfaces of head and neck area.
- vermilion lesions are common and are most often seen on lower lip
- intraorally, lateral and ventral tongue,oral floor and soft palate are most frequently involved.
- Symptoms-asymptomatic
- Signs
- Nonelevated,red macule or patch on an epithelial surface.
- Exact cause of red appearance is unknown, but may be related to an increase in number of underlying bloodvessels through which blood flows,which in turn may be secondary to localised inflammatory or immunological response caused by the dysplastic i.e,foreign epithelial cells.
- In some cases, color may result from a lack of surface keratin or extreme thinness of the epithelium.
- Homogenous form
- Commonly found on buccal mucosa and soft palate.
- Appears as bright red,soft,velvety lesion with straight or scalloped,well-demarcated margins.
- Often quite extensive in size.
- Size- typical lesion less than 1.5cm in greatest diameter
- Margins-sharply demarcated usually from surrounding pink mucosa and surface is smooth and regular in coloration.
- Granular or speckled form-soft,red lesions that are slightly elevated with irregular outlines and granular or finely nodular surface speckled with tiny white plaques.
- Erythroleukoplakia
- Erythroplakia interspersed with patches of LP in which erythematous areas are irregular.
- Borders may be well circumscribed or blend impercibly with surrounding oral mucosa.
- In such lesions, red areas are the sites most likely to contain or develop dysplastic cells and therefore should be the area of biopsy.

- Incisional biopsy is the preferred method of obtaining a microscopic diagnosis. Excisionalbiopsy of a potential malignancy may result in under treatment and violation of surgical oncologic principles.
- The definitive treatment remains controversial. A conservative surgical procedure such as mucosal stripping is often performed with minimal damage to deeper connective tissues. This has the distinct advantage of preserving tissues for microscopic evaluation of potential regions of invasion.
- Destructive techniques like laser ablation,electrocoagulation and cryotherapy are also effective.
- The key to therapy is extended clinical follow-up. Patients shold be examined every 3 months fof the first postpperative year and every 6 months for an additional 4 years. After that, an annual re-evaluation with a thorough head and neck examination is advisable.
- Elimination of a suspected irritant.

ORAL LESIONS ASSOCIATED WITH TOBACCO USE

SMOKER’S PALATE ORSTOMATITIS NICOTINA

- Causes- seen in heavy pipe and cigar smokers and is most common in males. It is most commonly seen in reverse smoking habit.

- Appearance-redness and inflammation of palate.
- Signs
- Palate develops diffuse,grayish-white,thickened,multinodular papular appearance.
- There is a small red spot inthe center of each tiny nodule representing a dilated and sometimes partiallyoccluded orifice of an accessory palatal salivary gland duct around which inflammatory cell infiltration is prominent.
- The epithelium around the duct shows excessive thickening and keratinisation.
- Surface-fissures and cracks may appear producing a wrinkled,irregular surface.
- Clinical types
- Mild-red,dot like opening on blanched area.
- Moderate-characterised by well defined elevation with central umbilication
- Severe-marked by papules of 5mm or more with umbilication of 2-3mm
- Palatal changes in reverse smokers are diverse
- Keratosis-diffuse whitening of entire palatal mucosa
- Excrescences-1-3mm elevated nodules often with central red dots corresponding to the opening of palatal mucous glands.
- Patches-well-defined,elevated white plaques which could qualify for the clinical term leukoplakia
- Red areas-well defined reddening of palatal mucosa.
- Ulcerated areas-crater like areas covered by fibrin
- Non-pigmenteed areas-area of palatal mucosa which is devoid of pigmentation

SNUFF DIPPER LESION

- 4 specific types clinical lesions are seen:
- Hyperkeratosis or erythematous lesion of oral mucosa
- Gingival and periodontal inflammation
- Combination of above
- Cervical erosion of teeth
- Location: it occurs on mucosal surface where snuff is habitually held. The compound N-nitroso-nor-nicotine(NNN) which is partly derived from bacterial action on nicotine during the curing process,is contributed by action of salivary nitrites,when tobacco is held in the mouth;occurs in greater concentration in snuff tobacco.
- Leukoplakia:lesion has wrinkled appearance.
- Prognosis:if habit is eliminated, majority of lesion disappears in 2 weeks.
- Long exposure to snuff results in malignant changes.

CIGARETTE SMOKER’S LIP LESION

- Appearance-generally flat or slightly elevated nodular white lesion on one or both lips correcsponding to site at which cigarette is held and apparently smoked to a very short length nearing the butt of the cigarette.
- Signs: increasd redness and stippling of lip in localised area
- Margins-it has elliptical,circular or irregular borders.
- Color: pale to white and slightly elevated with nodular or papillary shape.

BOWEN’S DISEASE

It is localised ‘intraepidermoid carcinoma’that may progress to invasive carcinoma over many years which is characterised by progressive scaly or crusted plaque like lesion.

Causes

- Sun exposure

- Arsenic ingestion

Clinical features

- Sites:occurs on male and female genital mucosa and in oral mucosa as erythroplakia, leukoplakia or erythematous lesion.

- Appearance:appears as slowly enlarging erythematous patches with little to suggest the malignant process.

- Skin: there is a red and slightly scaly area on the skin, which eventually enlarges and turns into white or yellowish lesion.

- Signs: when these scales are removed it produces a granular surface without bleeding.

Management

Use of freezing technique,diathermy,cauterization,radiotherapy or application of cytotoxic drugs.

Precancerous conditions

Oral sub mucous fibrosis

It is a chronic progressive, scarring disease that predominantly affects people of South East Asian population. This condition was prevalent in the days of Sushruta (600 BC), who labeled this condition as “Vidhari”. Schwartz in 1952 described this condition as “Atrophica idiopathic mucosae oris”.

Epidemiology:

The prevalence rate of oral sub mucous fibrosis in India, Burma,and South Africa Ranges from 0 to 1.2% .in India the overall incidence is between 0.2% to 0.5%. Clinical features:

Age and sex distribution: it affects both sexes. Recent data shoes male predominance. Age ranges between 15 to 50 yrs.

Oral sub mucous, fibrosis involves all parts of oral mucosa however , most common site is buccal mucosa (98 %) and retro molar area. Other sites commonly involved are soft palate(49%) , palatal fauces, uvula, tongue(37%) , and labial mucosa ( 36%).

Prodromal symptoms: burning sensation in the mouth, intolerance to spicy food, appearance of vesicles especially on the palate, ulcerations or recurrent generalized inflammation of the oral mucosa , excessive salivation, defective gustatory sensation and dryness of the mouth . There are periods of exacerbations manifested by the appearance of small vesicles in the cheek and palate. The interval between such exacerbations varies from three months to one year. Focal vascular dilations manifest clinically as petichae in the early stages of the disease. On palpation, pain in areas where fibrotic bands are developing.

Advanced OSF: as the disease progresses, the oral mucosa becomes blanched and slightly opaque, and white fibrous bands appear. The buccal mucosa and lips may be affected at an early stage. Fibrous bands in the buccal mucosa run in a vertical direction. The density of the fibrous deposit varies from a slight whitish area on the soft palate, causing no symptoms, to a dense fibrosis, causing fixation and shortening or even deviation of uvula and soft palate. The fibrous tissue in the faucial pillars ranges from a slight sub mucosal accumulation in both pillars to dense fibrous extending deep into the pillars with strangulations of the tonsils. It is this dense fibrosis , involving the tissues around the pterygomandibular raphae, that causes varying degrees of difficulty in mouth opening. Upon palpation a circular band can be felt around the rima oris and these changes are quite marked in the lower lip. In severe labial involvement the opening of the mouth is altered to an elliptical shape. With progressing fibrosis, the stiffening of certain areas of mucosa occurs leading to difficulty in opening the mouth, inability to whistle and difficulty in swallowing. When the fibrosis involves the nasopharynx, the patient may experience referred pain to the ear and a nasal voice as one of the later signs in some patients. Patient with advanced disease sometimes complains of dysphagia.

Localized blanching: Blanching is caused by the impairment of the local vascularity. The disease often starts as a blanched area and palpable fibrous bands develop over time. Blanching may be localized i.e., limited to an area, diffuse or reticular. The period between the initiation of the habit and the development of submucous fibrosis (incubation period) may range from few months to several decades. This variation may be due to the type of areca-nut chewing habit in addition, to variation in individual response and other unknown factors. For example, in those persons who chew only areca nut (supari), the incubation period is comparatively short, while in betelquid chewers, it is generally long.

Diffused blanching: In diffused blanching a greater part of the oral mucosa is involved. Blanching may be asymptomatic or accompanied by a burning sensation of the oral mucosa, and salivary changes.

Reticular blanching: Reticular (lace-like) blanching consists of blanched areas with intervening, clinically normal mucosa, giving it a lace-like appearance. Over a period of time one type of blanching may change into another. Microscopically, biopsies from the blanched mucosa without palpable fibrous bands (not yet categorized as sub mucous fibrosis) show features suggestive of early sub mucous fibrosis. Nevertheless, to avoid over- diagnosis, sub mucous fibrosis should be diagnosed only on the basis of the presence of palpable fibrous bands.

Sub mucous fibrosis at different intra oral locations:

Buccal mucosa: most commonly involved site 98%. The affected buccal mucosa becomes coarse and inelastic. In advanced cases, the mucosa becomes tough and leathery, with numerous vertical fibrous bands. Involvement of the buccal mucosa can be graded as mild, moderate, and severe, depending on the extent and prominence of fibrous bands.

Labial mucosa:

Sub mucous fibrosis can affect any or all parts of the oral mucosa. However, in certain geographic areas of India, some intraoral sites are more frequently affected than others. Overall, the labial mucosa is involved in about 36% of the cases. The affected mucosa is blanched, becomes rubbery, and exhibits difficulty to Evert.

Tongue involvement: The initial change in sub mucous fibrosis of the tongue is depapillation, usually towards the lateral margins. This feature may be accompanied by blanching and other symptoms. Blanching may involve the ventral surface or the entire tongue.

The floor of the mouth: When affected, the floor of the mouth is blanched and inelastic.

The soft palate: Involvement of the soft palate is marked by fibrotic change and a clear delineation of the soft palate from the hard palate as if a "heavy curtain" is hanging from the hard palate

The uvula: when involved the uvula is sunken, and in extreme cases it becomes bud like.

The gingiva: When the gingiva is affected, it is fibrotic, blanched and devoid of its normal stippled appearance.

Associated features:

Pigmentatory changes: A variety of associated features are seen in sub mucous fibrosis. Of these, hyper pigmentation or loss of pigmentation is very common. Many a times pigmentatory changes on the vermilion border are so striking that this disease can be suspected even before examining the oral cavity.

Vesicle: The presence of vesicles or a history of vesicle formation is reported in 32% of the cases. These vesicles are small and sub epithelial; they rupture easily because of the masticatory trauma. Often, there is a history of vesiculation following the intake of spicy food, suggesting an allergic reaction to spicy food. Certain histologic features of the vesicle also suggest an allergic reaction. There is no evidence, as yet, to implicate allergic response as the primary pathogenic mechanism in sub mucous fibrosis.

Ulceration: Patients with sub mucous fibrosis often complain of ulceration which is more marked in advanced cases. Microscopically, the epithelium is atrophic in this condition, and in advanced cases it is often “ribbon – like” .this possibly renders the epithelium fragile and vulnerable to ulceration.

Petechiae: Petechiae are small, raised reddish purple-spots that occur in the mucosa in various disorders. Petechiae may be a few or many, and they occur most commonly on the tongue. The labial and the buccal mucosa. Petechiae in sub mucous fibrosis do not represent a hematologic disorder; they occur due to the loss of connective tissue support to the juxtaepithelial vasculature, leading to their dilatation and the extravasation of blood into the tissue. The petechiae are transient in nature, and no specific treatment is necessary.

Differential diagnosis

Iron deficiency anaemia

Leukodema

Radiation fibrosis

Oral manifestations of scleroderma

Natural history

Unlike precancerous lesions, sub mucous fibrosis is not known to regress, either spontaneously, or with the cessation of the areca-nut chewing habit. This condition may either remain stationary or become severe, and also involve additional areas of the oral mucosa. The most serious aspect of this disease is the high risk for the development of oral cancer. As mentioned previously, the epithelium is atrophic in this condition which renders it susceptible to the action of carcinogens.

The observations upon which sub mucous fibrosis is considered precancerous are:

(1) Higher prevalence of leukoplakia in sub mucous fibrosis patients (26% versus 1-4% in the general population)
(2) Coexistence of submucous fibrosis and oral cancer
(3) Higher frequency (26%) of epithelial dysplasia;
(4) High incidence of malignant transformation and
(5) The histological diagnosis of oral cancer in sub mucous fibrosis without clinical suspicion for it.

Sub mucous fibrosis and coexistent leukoplakia: Leukoplakia is a precancerous! lesion; its coexistence with sub mucous fibrosis implies the high risk for oral cancer in sub mucous fibrosis patients. More frequently, homogeneous and nodular leukoplakia occur in sub mucous fibrosis

Sub mucous fibrosis and coexistent oral cancer: Not uncommonly (in 5% to 42% of the cases), sub mucous fibrosis and oral cancer coexist .As sub mucous fibrosis is generally a disease of long duration, the presence of oral cancer implies that it is a later development, i.e., a consequence of the malignant transformation of sub mucous fibrosis.

Malignant transformation: Atrophic epithelium first becomes hyperkeratosis and later, intracellular edema and basal cell hyperplasia develop eventually, following epithelial atypical with moderate epithelial hyperplasia and then, carcinoma can develop at any time.

The WHO collaborating center for oral precancerous lesions has concluded that although oral sub mucous fibrosis predisposes to cancer, it is not absolutely occlusive. It is highly probable that such relationship does exist.

Long-term population based studies have confirmed the precancerous nature of sub mucous fibrosis. A study showed a very high relative risk for the development of oral cancer in sub mucous fibrosis when compared to individuals who had tobacco habits, but did not exhibit any lesions. In sub mucous fibrosis patients, cancer may develop from locations which are otherwise uncommon for cancer, for example, the dorsum and tip of the tongue, indicating the strong influence of the disease in malignant transformation

Management:

Supportive treatment:

- Vitamin rich diet: vitamin rich diet along with iron preparation.

- Iodine B complex preparation – the combination of iodine compound with vitamin B complex is responsible for the stimulation of metabolic process and enzymatic process within the body.

- Injection of arsenotyphoid and iodine – it is a fibrin dissolving agent.

Steroids

Local – hydrocortisone injection along with procaine hydrochloride injection locally in the area of fibrosis

Systemic- a therapy with hydrocortisone 25mg tablet, in doses of 100mg /day is useful in relieving burning sensation without untoward effects. This can be supplemented by local injection of hydrocortisone 25mg biweekly at the site. Increased vascularity of the site is observed, which is attributed to fibrinolytic, anti allergic and anti-inflammatory action of corticosteroid.

Placental extract:

The aqueous extract of placenta acts as biogenic stimulator. It accelerates cellular metabolism, aids in absorption of exudates, and stimulates regenerative process, increases physiological function of organs, produces significant enhancement of wound healing, and it has notable anti-inflammatory effect.

The region affected with sub mucous fibrosis is divided into 5 regions. Each region is locally injected around fibrous bands, intramuscularly, at the interval of 3 days for 15 days. Each time 2ml solution is deposited. This course can be repeated after a month, if required.

Hyaluronidase

Improvement in health of mucous membrane, burning sensation and trismus was observed by using hyaluronidase injection. Hyaluronidase decreases cell formation by virtue of its action on hyaluronic acid, which plays an important role in collagen formation.

Lycopene

Antioxidant from tomato extract.

Dose tab lycopene 200mcg. The drug should be given for a period of three months duration

Vitamin E

Vitamin E prevents the oxidation of essential cellular constituents such as the formation of oxidation product. It improves survival of erythrocytes. It also protects various drugs, metals and chemicals and acts as scavenger of free radical.

Other therapies :

Vasodilator injection- relives the ischemic effect and helps the nutritional and therapeutic measures to reach the affected tissues, with use of fluorouracil.

Injection of interferon gamma- intralesional injection of interferon gamma improved mouth opening and reduce mucosal burning.

Surgical management

Conventional

Surgical treatment is the method of choice; when there is marked limitation of opening of the mouth , in cases where biopsy reveals neoplastic changes and when there is marked trismus and dysphagia .

Laser

CO2 laser alleviates the functional restriction, when compared to traditional surgical technique and subsequent grafting.

cyrosurgery

local destruction of tissue by freezing it in situ. Open liquid sprays are better suited for mucosal lesion that are extensive a superficial and do not involve the basement membrane.

Oral physiotherapy

Advised in early and moderately advanced cases. This includes mouth opening and ballooning of mouth. Forceful mouth opening have tried with mouth gag acrylic surgical screw.

Diathermy

Microwave diathermy is useful in some early or moderately advanced stages. Low current is used (20 watts x 2450 cycles). It acts by phsiofibrinilysis of bands. Its value is increased if it is combined with other treatment.

Lichen planus

Introduction

Lichen planus is primarily a dermatologic disorder in which various mucosal surfaces may be involved either independently, concurrently with cutaneous involvement, or serially.

About half of the patients with skin lesions have oral lesions, whereas about 25% present with oral lesions alone. Oral lichen planus is a chronic disease that can persist in some patients for a long time. In contrast to cutaneous lichen planus, the oral form may persist for up to 25 years. Oral lesions may coexist with lesions of the genital mucous membranes or with lesions of cutaneous lichen planus.
. It was first described by Wilson in 1869 and is thought to affect 0.5-1% of the world's population

The prevalence of oral lichen planus in random population samples in India varies from 0.1% to 1.5%. Although various factors are suggested to be involved in the pathogenesis of this disease, its exact etiology is still not clear. Interestingly, 93% of individuals with oral lichen planus are tobacco users and a majority of them chew as well as smoke tobacco. Tobacco use also influences the natural history of oral lichen planus. Although tobacco is not considered as an etiologic agent for this condition, these observations are relevant in the management of oral lichen planus cases.

The precancerous nature of oral lichen planus is still uncertain. Currently, this condition is categorized as a "probable precancerous condition". Longitudinal studies on oral lichen planus patients from India demonstrated a high but statistically insignificant excess risk for oral cancer in this condition. Therefore, a careful long-term observation of oral lichen planus patients is highly desirable. The relative risk for oral lichen planus was highest (13.7) among those who smoked and chewed tobacco.

Clinical features

Oral lichen planus is a disease of adulthood, and children are rarely affected. It is usually observed in nervous, `highly strung' people (Shaler 1983). Oral lichen planus is diagnosed on the basis of the presence of Wickham's striae that can be faint or prominent. Several pearly white papules which are the basic eruptive elements in this condition can also be discerned in the striae or, occasionally, oral lichen planus may entirely consist of these papules. Oral lichen planus like its cutaneous counterpart, occurs in various morphologic forms..

It may manifest anywhere in the oral cavity. The buccal mucosa. tongue, and gingiva ale the most common sites, whereas palatal lesions are uncommon. They are usually symmetrical and bilateral lesions or multiple lesions in the mouth are common. Andreasen (1968) divided oral lichen planus into six types: reticular, papular, plaque-like, erosive, atrophic, and bullous. The reticular, papular, and plaque-like forms are usually painless and appear clinically as white keratolic lesions. The erosive, atrophic, and bullous forms are often associated with a burning sensation and in many cases can cause severe pain. A detailed history and observation of the clinical features of the disease are usually sufficient to establish the diagnosis. Malignant transformation of oral lichen planus remains controversial.

The buccal mucosa is the most frequently (84%) affected site. Genearally, oral lichen planus is asymptomatic. Patients with erosive lichen planus, however, may experience burning sensation or even pain at the affected area.

Reticular form :
This is the most common form of lichen planus. Characteristically, it presents as a series of' line, radiant, white striae known as 'Wickham striae', which may be surrounded by a discrete erythematous border. The buccal mucosa is the site most commonly involved. The striae are typically bilateral in a symmetrical form on the buccal mucosa. They may also be seen on the lateral border of tongue and less often on the gingiva and the lips. Reticular lichen planus is likely to resolve in 4l % of cases.

Papular form

This form presents as small white pinpoint papules about 0.5 mm in site. It is rarely seen and being small, it is possible to overlook them during a routine oral examination.

Plaque form : The plaque form of lichen planus consists of either a pearly white or grayish white plaque ( Fig. 3). At times , it is difficult to distinguish a plaque form of oral lichen planus from a leukoplakia solely on clinical basis. The presence of Wickham’s striae, papules or other morphological forms may often help in distinguishing it from leukoplakia; the plaque like form may range from a. slightly elevated and smooth to a slightly irregular form and may be multifocal. The primary sites arc over the dorsum of the tongue and the buccal mucosa. Plaque like oral lichen planus resolves in only 7% of cases. This form is significantly more common among tobacco smokers.

Atrophic form:

The atrophic type is diffuse, red and there arc usually white striae. Such striae that radiate peripherally are usually evident at the margins of the atrophic zones of the lesion. The attached gingiva is often involved and the condition is commonly referred to as `chronic dcsquamative gingivitis'. The lingual gingiva is usually less severely involved. This condition can cause a burning sensation particularly when in contact with certain foods. About 12% of the atrophic lesions will resolve spontaneously.

Bullous form

Appear as small bullae or vesicles that tend to rupture easily. The bullae or vesicles range from a few millimeters to several centimeters in diameter. When they rupture they leave an ulcerated, painful surface. This form is rarer than the other firms of oral lichen planus. The bullous form is commonly seen on the buccal mucosa, particularly in the postero-inferior areas adjacent to the second or third molar teeth. The next most common site is the lateral margin of the tongue. The lesions are rarely seen on the gingiva or inner aspect of the lips.

Erosive form : Erosive form of lichen planus consists of erosions of various sizes on the oral mucosa .Often, Wickham’s striae or papules can be discerned on the erosion.

About 20% of oral lichen planus cases exhibit erosive or atrophic areas. Erosive lichen planus may cause burning sensation or pain of the oral mucosa and it often runs a

prolonged course. Erosive lichen planus shows a higher risk for cancer development, when compared to other variants of oral lichen planus.

Annular and linear forms: Annular and linear forms consist of striae that occur in a circular and linear fashion.

Oral lichen planus associated with pigmentation: In about 11% of cases, oral lichen planus may be associated with pigmentation. It may begin

Either with pigmentation or the pigmentation may appear subsequently. While the appearance of pigmentation in cutaneous lichen planus indicates the resolution of the condition, no such conclusions can be made in regard to its oral counter part.

Multiple forms: Occasionally, several forms of oral lichen planus may coexist,

And one form may change into another over time

Natural history

Oral lichen planus may remain stationary (in 87% to 93% cases), regress spontaneously (in 7% to 13% cases) and recur in about 3% of the cases. Malignant transformation was also observed in few cases of oral lichen planus

Malignant transformation:

There is some controversy regarding its malignant potential. There seems to he a slightly higher incidence of oral squamous cell carcinoma is patients with oral lichen planes than in the general population. The actual overall frequency of malignant transformation is low, varying between 0.3% and 3%. The farms that more commonly undergo malignant transformation are the erosive and atrophic forms.

Diagnosis

Clinical diagnosis- the interlacing white striae appearing bilaterally. Presence of Wickham striae and koebner phenomenon is also diagnostic

Laboratory diagnosis- there is hyperorthokeratosis, hyperparakeratosis, acanthosis with intercellular edema of spinous cells. Biopsy also shows civatte bodies in spinous and basal cell layers and lamina propria. Saw tooth rete pegs are also seen

Differential diagnosis

The different diagnosis should include

lichenoid reactions,

leukoplakia,

squamous cell carcinoma,

pemphigus,

mucous membrane pemphigoid, and

candidosis

Lupus erthyematosus

Lichenoid reactions in the oral cavity are invariably drug induced lesions. in some cases, erythema multiforme can resemble bullous lichen planus, but it is more acute and generally involves the labial mucosa.

A detailed description of the clinical characteristics and the distribution of the lesions are usually sufficient to differentiate oral lichen planus from other similar diseases

Management

Removal of cause- the causative factor is removed and this may lead to resolution of lesion subsequently .

Steroids- the rationale behind their use is their ability to modulate inflammation and immune response .

Topical application of antifungal agent – it is given when candidiasis superimposed lichen planus.

Vitamin A - anti-keratinizing and immunomodulating effects.

Cyclosporine - it is a selective inhibitor of CD4 helper T lymphocytes that is used systemically to achieve immunosuppression .

Surgical therapy- it is indicated when conventional methods fail in ulcerative lesion and small solitary lesions.

Psychotherapy emotional status plays an important role in etiology of this disease. In some cases, the lesion may regress when the patient is made aware of psychogenic implication of the condition and the nature of emotional stress is understood .

Dapsone therapy - used in severe form of erosive lesions. Help to control lymphocyte mediated progress of lichen planus by modulating the release of inflammatory or chemo tactic factor for mast cells or neutrophils .

PUVA therapy – psoralens and high intensity long wave ultraviolet A (PUVA) light is used as a therapeutic agent .

Fluocinonide- fluocinonide is an adhesive base can be useful in treating lichen planus.

Symptomatic treatment can be provided by giving analgesics, topical anesthetic, and anti-histamine rinse.

Others- various other agents are used in treatment of lichen planus. It includes vitamin B complex, heavy metal preparation, such as those containing bismuth, arsenic, and mercury, antibiotics, such as penicillin, doxycycline, radiation, chloroquine therapy and immunization therapy.

Dyskeratosis congenita

It is also known as “ Zinssner – Engman – Cole syndrome”. It is a well recognized but rare genokeratosis. It is a X-linked disorder characterized by a series of oral changes that lead eventually to an atrophic leukoplakic oral mucosa,with the tongue and cheek most severely affected.. The

Oral changes occur in association with severely dystrophic nails and a prominent reticulated hyperpigmentation of the skin of the face, neck, and chest.. Many cases also exhibit hematologic changes including pancytopenia, hypersplenism, and an aplastic or Fanconi’s anemia .The oral lesions commence before the age of 10 years as crops of vesicles with associated patches of white ulcerated necrotic mucosa often infected with Candida. Erythroplakic changes and nail dystrophy follow, with leukoplakic lesions and carcinoma supervening on the oral lesions in early adulthood.

Clinical features

Age and sex distribution: it is evident during first 10 years of life. It is almost exclusively seen in males.

Nail changes – nail changes are the first manifestation, becoming dystrophic and shedding some time after the age of 5 years.

Pigmentation – grayish brown pigmentation appear in some time which is seen usually on trunk , neck and thigh.

Skin – the skin may become atrophic , telangietatic and face appears red.

Thrombocytopenia- it is developed during second decade of life.

Other features – other minor manifestations are frail skeleton, mental retardation, small sella turcica, dysphagia, transparent tympanic membrane, deafness, epiphora, eyelid infection, urethral anomalies, small testes and hyperhydrosis of the palms and soles.

Oral manifestations

Sites – most common sites are tongue and buccal mucosa

Appearance – it appears as diffusely distributed vesicles and ulcerations followed by accumulation of white patches of necrotic epithelium and sometimes , superimposed monolial infection. There is also atrophy of tongue,

Recurrent ulceration – after sometime, in the age group of 14 to 20 years, there are repeated recurrent ulceration and development of erythroplakia or red mucosal lesion

Erosive leukoplakia – finally between the age of 20 and 30 years, there is development of erosive leukoplakia and carcinoma.

Radiographic features

There may be severe periodontal bone loss

Diagnosis

Clinical diagnosis leukoplakic type lesion associated with nail changes and pigmentation will diagnose dyskeratosis congenita

Laboratory diagnosis. - The skin lesions show increased number of melanin containing chromatophores and increased vascularity. There is anaemia, leucopoenia, thrombocytopenia and pancytopenia.

Management

Periodic check up

Periodic check up should be done for evidence of malignant transformation

Lupus erythematoses

Characterised by presence of abnormal antibodies and immune complex.

Types

Discoid or cutaneous lupus erythematosus – confined to skin and mucosa

Systemic lupus erythematoses-if there is multi organ involvement

Etiology

Genetic predisposition

Immunological abnormality possibly mediated by viral infection-immune complex consisting chiefly of nucleic acid and antibody account for majority of the tissue changes.

Autoimmune disease

Endocrine- there is high incidence in females in pregnancy.

Biochemical increase in excretion of metabolic products , particularly tyrosine and phenylalanine in certain SLE patient.

Discoid lupus erythematosis

Clinical features

Age & sex – it occurs in 3rd and 4th decades, female predilection in the ratio 5:1

Site – most common sites are face , oral mucosa, chest, back, extremities.

Appearance – it is circumscribed, slightly elevated, white patch that may be surrounded by red telangiectatic halo

Cutaneous lesion – cutaneous lesions are slightly elevated red or purple macules; that are often covered by gray or yellow adherent scales.

Carpet track extension- forceful removal of scale results in ‘carpet track extension ‘which has dipped into enlarged pilosebaceous canals.

Peripheral growth- the lesion increases in size by peripheral growth. periphery of the lesion appears pink or red , while the centre exhibits an atrophic scarred appearance.

Butterfly distribution

Butterfly distribution on macular region and across the bridge of the nose.

Oral manifestations

Sites- most common sites are buccal mucosa, tongue, palate and vermilion border of lip.

Symtoms- there may be burning and tenderness which may be intermittent or disappears if the lesion becomes inactive.

Appearance – it begins as erythematous area, sometimes slightly elevated, but more often depressed, usually with induration and typically with white spots. Occasionally superficial painful ulceration may occur with crusting or bleeding, but no actual scale formation is seen.

Margins – the margins of the lesion are not sharply demarcated. Fine white striae radiate out from the margins.

Central healing- central healing may result in depression.

Lip- erythematous , atrophic plaque , surrounded by keratotic

Systemic lupus erythematosis

Clinical features

Age and sex it occurs in 3rd (female) and 4th( male) decades and has female predilection (8: 1)

Sites: it is characterised by repeated remissions and exacerbations with common sites being face, neck, upper arm , shoulders and fingers

Symptoms it is manifested by symptoms of fever and pain in the muscle and joints. It may show as itching or burning sensation as well as area of hyperpigmentation. Severely intensifies after exposure to sunlight.

Butterfly distribution of lesion on face- the cutaneous lesion consists of erythematous patches on the face, which coalesce to form roughly symmetrical pattern over the cheeks and across the bridge of nose , is called butterfly distribution.

Skin lesions – skin lesions are widespread, bilateral with signs of acute inflammation. This findings helps to differentiate between skin lesions of DLE and SLE.

Kidney involvement – in kidney, fibrinoid thickening o glomerular capillaries producing the characteristic “wire loop” which may be sufficient to result in renal insufficiency.

Heart involvement- heart may suffer a typical endocarditis involving valves as well as fibrinoid degeneration of epicardium and myo cardium.

Oral manifestations

Site- most common sites are buccal mucosa ,lip, and palate.

Symptoms – complains of burning sensation , xerostomia, or soreness of mouth

Signs – lesions similar to DLE, expect that hyperaemia, edema and extension of lesion is more pronounced. Greater tendency to bleed and petechiae , suspected ulcerations surrounded by red halo.

Appearance the intraoral lesion is composed of a central depressed red atrophic area surrounded by 2 to 4 mm elevated keratotic zone that dissolves into small white lines.

Lupus cheilitis – the lip lesions appear with central atrophic area with small white dots surrounded by keratinized border , which is composed of small radiating white striae. There is occasional ulceration of central area.

Diagnosis

Clinical diagnosis – skin lesion with lesion present on oral mucosa which atrophic and erythematous will suspect lupus erythematous. Oral and nasopharyngeal ulceration is major diagnostic criteria for SLE.

Laboratory diagnosis- LE cell inclusion phenomenon with surrounding pale nuclear mass apparently devoid of lymphocytes. Anaemia, leukopenia and thrombocytopenia, with sedimentation rate increased. Serum gamma globulin increased and coombs test is positive.

Positive lupus band test- it shows deposition of IgG, IgM, or complement component in skin.

Dental consideration

Thrombocytopenia – it may be sometimes severe. The result of a recent platelet count should be studied before undertaking oral surgery.

Bacterial endocarditis – libman-Sacks vegetation under the mitral valve may occur in patients with SLE , it can lead to bacterial endocarditis . so patients with SLE should have antibiotic prophylaxis before dental treatment that is likely to cause bacteremia.

Exacerbation by drug therapy- drugs that have been related to exacerbation include penicillin, sulphonamide and NSAIDs with photosensitizing potential.

Exacerbation by surgery- all elective surgeries including dental procedures to be avoid.

Susceptibility to shock and infection – patients with SLE may be taking adrenal suppression dose of corticosteroids or cytotoxic drugs and hence, they may be susceptible to shock and infection.

Differential diagnosis

Lichen planus

Lichenoid reaction

Ectopic geographic tongue

Psoriasis

Electrogalvanic lesion

Leukoplakia and erythroplakia

Georgraphic stomatitis

Benign mucous membrane pemphigoid

Management

Corticosteroid- systemic lupus erythematous should be treated by systemic corticosteroid therapy and should be managed by physician. Discoid lupus erythematosis should be treated with topical steroid.

Anti-malarial drugs- anti-malarial drugs like hydroxylchloroquine combined with NSAID agents is also effective treatment modality.

Prevention- patient should avoid exposure to sunlight as this can aggravate the conditions.

Cheilitis Glandularis

Etiology

Chronic exposure to dust, wind and dust, Use of tobacco, Emotional disturbances and Inflammation of enlarged heterotrophic salivary glands.

Types

Simple, superficial suppurative type and deep suppurative type.

Clinical features

Common in adults in lower lip which becomes enlarged, firm and finally everted.viscid mucous secretion may seep from orifices of inflamed secretory ducts. Labial salivary glands become enlarged and nodular.

Plummer-Vinson syndrome

It is a disease of the Western Europe, so not discussed here.

Central papillary atrophy of tongue

[Median Rhomboid glossitis]

It was thought to be a developmental defect resulting from an incomplete descent of tuberculum impar and entrapment of a potion between fusing lateral halves of tongue. Common in male with age ranging from 5-84 years, located just anterior to foramen caecum on dorsal surface of tongue in midline and anterior to circumvallate papillae. Appear as ovoid, diamond or rhomboid shaped reddish patch or plaque. Surface is dusky red and completely devoid of filliform papillae and usually smooth. Other surface may be coated or matted. Generally asymptomatic. Though it is not included in the list of oral pre-cancerous condition there are recent report of malignant transformation in this condition.

Syphilitic Glossitis

White patch seen on tongue in secondary syphilis. The spirochetes, causative agent for syphilis has predilection for the actively mobile tissues of tongue. This condition leads to diffuse vasculitis and progresses to obliterative endarteritis ,eventually resulting in a circulatory deficiency to lingual mucosa. This cause atrophy of fungiform and filliform papillae and result in bald smooth lingual surface. Shrinkage of lingual musculature results fissuring of tongue. Any condition which result in atrophy of oral mucosa predisposes to malignant transformation.

References

1. Tobaco-related Oral Mucosal Lesions and Conditions - Mehta. gupta

2.WHO Collaborating Centre for Oral Precancerous Lesions. Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 1978;46:518-39

3. Rajendran R. Oral lichen planus. J Oral Maxillofac Pathol 2005;9:3-5

4. Rajendran R submucous fibrosis etiology , pathogenesis and future research WHO Bulletin OMS. Vol 72 1994oral

4.Histopathology

HISTOPATHOLOGICAL FEATURES OF PRECANCEROUS LESIONS AND CONDITIONS

PRECANCEROUS LESIONS

1. Leukoplakia
2. Erythroplakia
3. Palatal keratosis associated with reverse smoking

LEUKOPLAKIA

- Microscopically, leukoplakia is characterized by hyperkeratosis, acanthosis, basilar hyperplasia and infiltration of the inflammatory cells in lamina propria.

- Evidence of epithelial dysplasia is found in only 5-25% of cases if all oral sites are considered.

- The histopathological alterations of dysplastic epithelial cells are

1. Loss of polarity of the basal cells.
2. Presence of more than one layer of cells having a basaloid appearance.
3. Increased nuclear cytoplasmic ratio.
4. Drop shaped rete processes.
5. Irregular epithelial stratification.
6. Increased number of mitotic figures( a few abnormal mitoses may be present.)
7. Presence of mitotic figures in the superficial half of the epithelium.
8. Cellular pleomorphism.
9. Nuclear hyperchromatism.
10. Enlarged nucleoli.
11. Reduction of cellular cohesion.
12. Keratinization of single cell or cell groups in the prickle layer.

-Epithelial dysplasia is usually divided into three categories-mild moderate and severe.

- Leukoplakia is a clinical diagnosis. Therefore a few of the above changes will qualify the diagnosis of a case histopathologically as compatible with leukoplakias.

ERYTHROPLAKIA

-The epithelium shows lack of keratin production and is often atrophic, but it may be hyperplastic. This lack of keratinisation especially, when combined with epithelial thinness, allows the underlying microvasculature to show through, thereby causing the red colour.

-The underlying connective tissue often demonstrates chronic inflammation.

- According to one large clinicopathologic investigation, 90% of erythroplakic lesions histopathologically represent severe epithelial dysplasia, carcinoma in situ or superficially invasive squamous cell carcinoma.

- Differentiation of erythroplakia with malignant change and other early cell carcinomas from benign inflammatory lesions of oral mucosa can be enhanced by the use of 1% toluidine blue(tolonium chloride) solution applied topically with a swab or as an oral rinse. This technique gives excellent results in detecting epithelial dysplasia with false negative(under negative) and false positive(over diagnosis) rates well below 10%.

PALATAL KERATOSIS ASSOCIATED WITH REVERSE SMOKING

- Hyperorthokeratosis, epithelial dysplasia and inflammatory cells in the connective tissue are some features.

- Also melanin deposits in lamina propria and atrophic epithelium in red areas were noted.

PRECANCEROUS CONDITIONS

1. Lichen planus
2. Oral submucous fibrosis
3. Sideropenic dysphagia
4. Syphilis
5. Discoid lupus erythematosus
6. Dyskeratosis congenita
7. Cheilitis glandularis
8. Epidermolysis bullosa
9. Xeroderma pigmentosum

ORAL LICHEN PLANUS

- Hyperparakeratosis or hyperorthokeratosis with thickening of the granular layer, acanthosis with intercellular oedema of the spinous cells in some instances, the development of a ‘saw tooth’ appearance of the rete pegs are the typical findings.

- Band like subepithelial mononuclear infiltrate consisting of F cells and histiocytes; and degenerating basal keratinocytes that form colloid(cirrate, hyaline, cytoid) bodies which appear as homogenous eosinophilic globules are consistently seen.

- Degeneration of basal keratinocytes and disruption of the anchoring elements of the epithelial basement membrane and basal keratinocytes weakens the epithelial –connective tissueinterface. As a result, histologic clefts, (Max- Joseph spaces) may form and blisters on the oral mucosa (bullous lichen planus) may be seen at clinical examination.

- B cells and plasma cells are uncommon findings.

- Immunoglobulin or complement deposits are not a consistent feature.

- In some instances, fibrinogen and fibrin are deposited in a linear pattern in the basement membrane zone.

- Direct immunofluorescent studies: Nearly all lesions react with antifibrinogen and exhibit an intensely positive fluorescence that outlines the basement membrane zone with numerous irregular extensions into superficial lamina propria.

The pattern of fibrinogen deposition in the absence of fluorescence by other reagents is sufficiently unique to be used as a diagnostic criterion for OLP

ORAL SUBMOUCOUS FIBROSIS

- The epithelial changes in different stages of OSF are predominantly hyperplasia (early) and atrophy ( advanced) associated with an increased tendency for keratinizing metaplasia
- Lesions involving palate predominantly showed orthokeratosis and those of the buccal mucosa, parakeratosis.
- High mitotic count in parakeratotic epithelium and the association with parakeratotic leukoplakia and atrophic epithelial changes predispose OSF to malignancy.
- Subepithelial changes: on the basis of stained H and E sections, OSF can be grouped into four clearly definable stages: very early, early, moderately advanced and advanced.
- These stages are based on the
- Amount and nature of the subepithelial collagen.
- Presence or absence of oedema.
- Physical state of mucosal collagen.
- Overall fibroblastic response.
- State of blood vessels.
- Predominant cell type in inflammatory exudates.
- As the condition progresses, the waveness of the collagen bundle disappears.
- A vascular response due to inflammation, apart from the connective tissue repair process hasbeen very commonly found in OSF. Normal, dilated and constricted blood vessels have been often seen in combination in the same section. Persistent dilatation has also been seen in many moderately advanced biopsies.
- A rise in mast cells occurs in the earlier stages of tissue reactions but in advanced cases the counts are fewer in number.
- Inflammatory seen are mainly lymphocytes and plasma cells.
- Connective tissue in advanced stages is characterized by submucosal deposition of extremely dense and avascular collagenous tisssues with variable number of chronic inflammatory cells.
- Epithelial dysplasia is found in 10-15% of cases submitted for biopsy and carcinoma is found in 5% of the sampled cases.
- Excessive fibrosis in the mucosa seems to be the primary pathology in OSF. Atrophic changes in epithelium are secondary.

PLUMMER-VINSON SYNDROME (SIDEROPENIC DYSPHAGIA)

- Epithelial atrophy with varying degrees of submucosal chronic inflammation is seen.

- In advanced cases, evidence of epithelial atypia or dysplasia may be seen.

SYPHILIS

-Characterized by atrophy of oral mucosa.

-Atrophic or interstitial glossitis is the most characteristic and important lesion of the syphilis and is due to endarteritis obliterans.

-In syphilitic glossitis,the surface of the tongue gets broken up by fissures due to atrophy and fibrosis of the tongue musculature; and hyperkeratosis frequently follows.

-The predilection for syphilitic glossitis to undergo carcinomatous transformation has been recognized for many years.

-The intraoral gumma most commonly involves the tongue and palate.

DISCOID LUPUS ERYTHEMATOSUS

- The skin lesions are characterized by hyperkeratosis often displaying keratin packed into the openings of hair follicles (“follicular plugging”).

- Degeneration of basal layer is frequently observed and underlying connective tissue supports patchy to dense aggregates of chronic inflammatory cells.

- In the deeper connective tissue, the inflammatory infiltrate often surrounds the small blood vessels.

- Oral lesions demonstrate hyperkeratosis, alternating atrophy and thickening of the spinous cell layer, degeneration of the basal layer and subepithelial lymphocytic infiltration.

DYSKERATOSIS CONGENITA

- Skin biopsy specimens from areas of reticulated pigmentation typically shows mild hyperkeratosis, epidermal atrophy, telangiectasia of the superficial blood vessels and melanophages in the papillary dermis.

- Interface changes have been reported, with mild basal layer vacuolization and a lymphocytic infiltrate in the upper dermis

- Oral lesions have not been thoroughly studied, but the leukoplakic lesions appear to be a non-specific hyperparakeratosis and hyperorthokeratosis and acanthosis. Depending on the stage of disease, the epithelium may show dysplasia. Exact nature of preceding vesicles and ulcers has not been described.

CHEILITIS GRANDULARIS

- No consistent or pathognomonic features of this disorder are seen at the microscopic level. Instead a diverse array of possible alterations can be seen in both the surface epithelium and the submucosal tissues.

- The minor salivary glands may appear normal, or they may exhibit various changes indicative of non-specific adenitis. These changes can include atrophy or distension of acini, ductal ectasia with or without squamous metaplasia, chronic inflammatory infiltration and replacement of glandular parenchyma and interstitial fibrosis.

- Suppuration and sinus tracts may be present in cases that involve bacterial infection.

- Other possible histologic findings include stromal edema, hyperemia, surface hyperkeratosis, erosion or ulceration.

XERODERMA PIGMENTOSUM

-The histopathologic features are relatively non-specific in that the cutaneous premalignant lesions and malignancies that occur are microscopically indistinguishable from those observed in unaffected patients.

EPIDERMOLYSIS BULLOSA

- The histopathologic features of epidermolysis bullosa vary with the type being examined.

- The simplex form shows intraepithelial clefting by light microscopy. The elastic, pre-elastic and oxytalan fibres in the connective tissue are normal.

- Junctional, dystrophic and hemidesmosomal forms show subepithelial clefting.

- Electron microscopic examination, which is still considered the “gold standard”, reveals clefting at the level of lamina lucida of the basement membrane in the dystrophic forms.

- In contrast, the hemidesmosomal form shows clefting just below the basal cell layer at its interface with lamina lucida.

- The underlying connective tissue shows an absence of elastic and oxytalan fibres in dystrophic, dominant type. The elastic, pre-elastic and oxytalan fibres in the connective tissue are increased in number in dystrophic, recessive type.

- Immunohistochemical evaluation of perilesional tissue may help to identify specific defects to classify and subtype the condition further.

- Molecular genetic analysis is now being used to confirm the diagnosis in some instances.

HISTOPATHOLOGY OF ORAL SQUAMOUS CELL CARCINOMA

In this monograph the histopathology of oral squamous cell carcinoma and variants alone are discussed.

Pindborg JJ et al in 1997 defined squamous cell carcinoma as “ a malignant epithelial neoplasm exhibiting squamous differentiation as characterized by the formation of keratin or the presence of intercellular bridges”.Epidermal carcinoma is the most common malignant neoplasm of the oral cavity.

- Considerable histologic variations are presented in intra oral intra or;a epdermoid carcinomas although in generalthey tend to b moderately well differentiated neoplasm with some evidence of keratinisation

- The we;; differentiated epidermoid carcinaoma consists of sheets and nests of cells with obvious origin from squamous carcinoma

- Squamous cell carcinoma arises from dysplastic surface epithelium and is characterized histopathologically by invasive islands and cords of malignant squamous epithelial cells.

- Invasionis represented by irregular extension of lesional epithelium through the basement membrane and not subepithelial connective tissue.individuall squamous cee and sheets or islandsof cells are seen to be thriving as independent entities within the connective tissue, without attachment to the surface epithelium.

- Invading cells and cell masses may extend deeply into inderlying adipose tissues, muscle or bone destroying the original tissue as they progress

- Lesionla cells may surround and destroy blood vessels and may invade into the lumina of veins or lyphatics

- Thery is often a strong inflammatoru or immune cell response to invading epithelium, and focal area of necrosis may be present.the lesional epithelium may is capable of inducing the formation of new small blood vessels (angiogenesis) and occasionally, dense fibrosis (desmoplasia or scirrhous change).

- Histopathological evaluation of the degree to which these tumours resemble their parent tissur (squamous epithelium)and produce theit normal product (keratin) is called grading.

- Lesions are graded ona three point ( grades I-III) or afour point scale( I-IV)

- The less differentiated tumours receive the higher numerals

- The histopathologic grade of a tumour is related somewhat to its biologica behaviour. In other words a tumour that is mature enoughto closely resemble its tissues of orifin seems to grow at a slightly slower pace and to metastatize later in its corse.sucha tumour is called low-grade, grade I ,well difeerentiated squamous cell carcinoma.

- In contrast, a tumour with much cellular and nuclear pleomorphism and with much cellular andnuclear pleomorphism and with little or no keratin production may be son immature that it becomes difficult to identify the tissue of origin.such atumour rapidly enlarges,metastatizes early in its course and is termed as high grade , grade III/IV, poorly differentiated or anaplastic.

- A tumout with amicroscopic appearance somewhere between these two extremes is labeled as moderately differntaited carcinoma.

A system of grading squamous cell carcinoma called Broder’s grading has been proposed that depends upon the percentage of anaplastic cells present in a tumor .according ly the following 4 grades are recognized

Grade I less than 25 % anaplastic cell

Grade II 25-50% anaplastic cell

Grade III 50 – 75% anaplastic cell

Grade IV more than 75% anaplastic cell.

VERRUCOUS CARCINOMA( ACKERMAN’S TUMOR ) ( SNUFF DIPPER’S TUMOR)

- Verrucous carcinoma is a low grade variant of oral squamous cell carcinoma

- Verrucous carcinoma has a deceptively benign microscopic appearance. It is charcterised by wide and elongated rete ridges that appear to “push” into the underlying connective tissue.lesions usually show abundant keratin ( usually para keratin0 production and a papillary or verriciform surface,parakeratin typically fills the numerous clefts/crypts (parakeratin plays) betweenthe surface projections.these projections may b long and pointed or short anf blunted.the lesional epithelial cells generally show a normal maturation pattern with no significant dgreeof cellular atypia

- There is frewuently an intense infiltrate of chronic inflammatory cells in the subjacent connective tissue.

- The histopathologic diagnosis of verrucous carcinoma requires an adequate incisional biopsy. Because the individual cells are not very dysplastic,the pathologist must evaluate the overall histopathologic confihuration of the lesion to arrive at an appropriate diagnosis.

- Adequate sampling also is impotant because as may as 20% of these lesions have routine squamouse cell carcinoma developing concurrently with in the verrucous carcinoma.

SPINDLE CELL CARCINOMA( SARCOMATOID CARCINOMA) (POLYPOID ACRCINOMA)

- Spindle cell carcinoma is a rare variant of squamous cell carcinoma characterized by dysplastic surface epithelium in conjunction with an invasive spindle cell element.

- The spindle cell carcinoma is composed predominantly of fascicle of anaplastic spindle shaped cell.some spindle cells may appear as obvious epithelial elements but others strongly resemble atypical mesenchymal cells.

- On rare occasions bone cartilage or muscle differentiation may be seen. Numerous mitotic figures often are present.

- The overall picture is similar to that of an anaplato\ic fibrosarcoma. Except for the often inconspicuous squamous element.

- The squamous component usually consists of carcinoma in situ of the overlying surface epithelium bu may appear as islands of dysplastoc squamous epithelium among the spindle cells.direct transition betweenthe two cells may be seen. Metastatic lesions may show only spindle cell, only squamous cells, ora combination of both.

- Serial sections may be needed to find areas of uniequivocal squamous cell carcinoma, and immunohistochemical techniques can be particularly useful in distinguishing . this tumour form mesenchymal spindle cell malignancies. The lesional cells of most mesenchymal tumours typically produce vimentin but not cytokeratin.\

- Approximately 2/3 of the cases of spindle cell carcinoma react with antibodies directed against cytokeratin and and equivalent number show vimentin immunoreactivity.

- Some cases also will be positive for carcinoembryonic antigen(CEA).

ADENOSQUAMOUS CARCINOMA

- Adenosquamous carcinoma is a rare variant of squamous cell carcinoma that is characterized. histopathologically by a combination of adenocarcinoma and squamous cell carcinoma.

- Adenosquamous cell carcinoma appears as an admixture of a surface squamous cell carcinomaand an underlying ductal adenocarcinoma.

- Intracytoplasmic mucin is noted by mucicarcinoma staing in most cases, making differntaition from mucoepidermoid carcinoma difficult but helping to distinguish adenosuamous cell carcinoma from forms of squamous cell carcinoma that exhibit a pseudoglandular pattern of degeneration

- Both squamous and glandular components immunoreact with antibodies directed against high molecular weight cytokeratosis.

BASALIOD SQUAMOUS CELL CARCINOMA

- Basaloid squamous cell carcinoma has two microscopic components.

- The first is a superficial well differentiated orr moderately differentiated squamous cell carcinoma often with surface ulceration,multifocal origin, and areas of carcinoma in situ.

- The seconf=d deeper component is an invasive basaloid epithelium arranged in islands,cords and gland like lobules.

- Theis deeper tumour often shows palisidinf pf peripheral cells necrosis of central regions,a nd occasional squamous differentiation.

- This component appears similar to basal cell carcinoma,adenoid cystic carcinoma,basal cell adenocarcinoma or neuroendocrine carcinoma.

- The interface between the two components is typically sharp and distinct , but the transition from squamous to basaloid cells may occasionally be seen.

- Basaloid cell and islands of cells often are surrounded by mucoid strooma(basal lamina material.

Normally H&E stained sections are only examined to make the diagnosis of oral squamous cell carcinoma. In highly undifferentiated immunohistochemical staining may be necessary to confirm the tissue of origin. 2 H.C.S are useful in confirmatory diagnosis of the are variants of squamous cell carcinoma

IMMUNOHISTOCHEMISTRY

- This is an immunological method of recognizing a cell by one or more of its specific components in the cytoplasm,cell membrane or nucleus. These cell components (called antigens) combines with specific antibodies on the formalin fixed parafiin sections or cytological smears. The complex of antigen-antibody on slide is made visble for light microscopic identification by either fluorescent dyes(fluorochormes) or by enzyme system( chromogen). The specifc antibody against a particular antigen is obtained by hybridoma technique by monoclonal antibody production.

- These monoclonal antibodies , besides being specific against antigen, are highly sensitive in detection of antigenic component, and therefore , impart objectivity to the subjective tuumour diagnosis made by the surgical pathologist.

- Though the list of immunohistochemical stains is over increasing one important group of such antibody stains is directed against various classes of intermediate filaments which is useful in classifications of poorly differentiated tumours of epithelial or mesenchymal origin.

Intermediate filaments and their significance in tumors diagnosis

Abbildung in dieser Leseprobe nicht enthalten

References

1) Oral & maxillofacial pathology -2nd edition Neville, Damm, Allen, Bouquot

2) Shafers textbook of oral pathology. 6th edition

5.Methods of oral cancer diagnosis

INTRODUCTION

Over 90% of oral and pharyngeal cancers are squamous cell carcinomas (SCCs).

Oral cancer consistently ranks as one of the top ten cancers worldwide, with broad differences in geographic distribution. Despite numerous advances in treatment, the 5- year survival of oral cancer patients remained approximately 50% for the last 50 years. This poor prognosis is likely due to several factors. First, oral cancer is frequently associated with the development of multiple primary tumors. The rate of second primary tumors in these patients, 3–7% per year, is higher than for any other malignancy. This characteristic led Slaughter to propose that multiple individual primary tumors develop independently in the upper aerodigestive tract as a result of chronic exposure of the lining mucosal epithelium to carcinogens, a theory known as ‘‘field cancerization’’. Although this theory is not accepted by all authorities, oral cancer patients who live five years after their initial primary disease is diagnosed and treated have up to a 35% chance of developing at least one new primary tumor during that time. To underscore the significance of this complication, the most common cause of treatment failure and death in oral cancer patients is their second primary tumor.

Second, poor survival among oral cancer patients can also be attributed to the advanced extent of the disease at the time of diagnosis, with over 60% of patients presenting in stages III and IV. Such dismal statistics seem perverse since the disease primarily arises in the surface oral epithelium that is readily accessible to direct visual and tactile examination. The conclusion that at least some lesions are ignored or missed by patients, health care professionals or both is inescapable. In part, this may be due to an incomplete understanding or awareness that even small asymptomatic lesions can have significant malignant potential.

One approach to this problem would be to improve the ability of oral health care professionals to detect relevant potentially malignant lesions or cancerous lesions at their earliest or most incipient stage. Another strategy would be the development and use of diagnostic aids that could help the general dentist or dental specialist more readily identify or assess persistent oral lesions of uncertain biologic significance.

METHODS IN ORAL CANCER DETECTION

There are several methods of early detection of oral cancer. They are:

I. Clinical methods.
II. Photodiagnosis.
III. Molecular methods.
IV. Histopathologic methods.

CLINICAL METHODS

These include:

1. Conventional Oral Examination (COE)
2. Examination after intravital staining.
3. Examination by tissue reflectance
4. Acridine binding method.

Conventional Oral Examination (COE)

A conventional oral examination (COE), using normal (incandescent) light, by a trained eye is probably the most acceptable screening test for oral cancer screening. Studies have reported a relatively high degree of sensitivity, specificity and positive predictive value of COE.

Although COE may be effective as a screening test, there are still many problems with this approach. First, approximately 5–15% of the general population has oral mucosal abnormalities. Without question, the vast majority of these lesions are clinically/biologically benign. Second, the classic clinical presentation of an oral malignancy or premalignant lesion: a red patch, white patch or persistent ulcer that cannot be diagnosed as any other condition, is well recognized. The problem, however, is that only a small percentage of those are progressive or become malignant and a COE cannot discriminate between these lesions and their nonprogressive counterparts. Some precancerous lesions may be lurking within mucosa that appears clinically normal by COE alone.

Physical examination is of special value in the detection of oral cancer. It provides an opportunity to identify tobacco-related oral conditions (halitosis, extrinsic discoloration of teeth, gingivitis, necrotizing ulcerative gingivitis, chronic periodontitis, loss of teeth, and precancerous and malignant oral and pharyngeal soft tissue changes). Inspection is the most common examination technique. It affords the examiner an opportunity to assess the character of oral mucosal tissues and observe any changes in color, evidence of pigmentations, altered vascularity, and loss of integrity. Palpation provides the examiner with additional information concerning the consistency of tissues, changes in texture, physical characteristics of masses, the presence or absence of tenderness and/or induration, and relation to anatomical structures. Lymph nodes usually felt and not seen should be evaluated for location, architecture (size, shape, symmetry, and discreetness), consistency, tenderness, mobility, or attachment. Adenopathy of a particular node is an indication of an abnormality that must be explained. Lymphadenopathy associated with intraoral pathosis of various sites involves chiefly the submandibular, submental, and anterior cervical chains. Pathologic changes in the cervical nodes, both inflammatory and neoplastic, may be difficult to distinguish from nonlymphatic tumors or degenerative changes. However, secondary involvement of a lymph node in the neck from a primary malignant lesion (characterized as matted, non tender, usually firm and fixed) of some oral epithelial structure is a most significant finding. Unilateral location indicates metastatic neoplasm and bilateral location indicates primary neoplasm.

Intravital Staining

Two methods:

i. Toluidine Blue method

ii. Lugol’s Iodine method

Toluidine Blue Staining

Toluidine blue (also known as tolonium chloride) is an acidophilic, metachromatic nuclear dye of thiazine group that selectively stains acidic tissue components particularly nucleic acid such as DNA and RNA. Hence, dysplastic and anaplastic areas which contains more DNA than normal cells are stained. Malignant epithelium contains intracellular canals that are wider than normal epithelium which also facilitates the penetration of dye. Most of the normal epithelial surfaces also stain blue after the application of 1% toluidine blue solution, but the stain is lost after application of 1% acetic acid solution. Benign ulceration has well defined uptake of dye at the margins whereas, diffuse marginal pattern is characteristic of dysplasia or malignancy.

It is available as a 3 component system. First contain 1% toluidine blue 10ml solution. Second and third kit contains 1% acetic acid as pre- and post-rinse solution. The system also contains absolute alcohol and distilled water with pH adjusted to 4.5.

The application of toluidine blue solution involves 4 steps:

- Rinsing – ask the patient to rinse the mouth twice with water (20 seconds each). After rinsing, ask the patient to rinse with 1% acetic acid for 20 seconds.

- Drying – gently dry the suspicious mucosal areas with gauze. Take care not to abrade the tissues while drying.

- Application of toluidine blue solution – apply 1% toluidine blue solution to the lesion with a cotton swab.

- Rinsing – ask the patient to rinse again with approximately 150ml of acetic acid for 1 minute, followed by water.

If the mucosa is stained positive, repeat the procedure in 1-2 weeks. Biopsy of the site is advised which stain positive on two successive visits.

It is not cancer specific, but it has been reported to stain cells with relatively increased amounts of DNA and possibly altered DNA in premalignant and malignant epithelial lesions. It has been used for decades as an aid to the identification of mucosal abnormalities of the cervix as well as in the oral cavity. It has been valued by surgeons as a useful way of demarcating the extent of a lesion prior to excision. Helps in determining the site of biopsy in large multicentric lesions. The sensitivity of toluidine blue staining for the detection of oral cancers has ranged from 0.78 to 1.00 and the specificity from 0.31 to 1.00. However, a low positive predictive value of 43.5% for potentially malignant lesions [10] and a false negative rate as high as 20.5% for pre-malignant lesions [8] also have been reported. Toluidine blue appears to be good at detecting carcinomas but is positive in only 50% of lesions with dysplasia. In addition, it also frequently stains necrotic tissues and common, benign conditions such as non-specific ulcers, hence the number of false positive sites will increase.

Lugol’s Iodine Staining

It is retained in normal squamous epithelial cells but not in dysplastic or malignant cells of the squamous epithelium. The use of toluidine blue in application in combination with Lugol’s iodine may offer potential advantage. The Toluidine blue will stain the abnormal (reactive and dysplastic) epithelium whereas, Lugol’s iodine solution will bind to glycogen present in normal epithelium. It produces a brown black stain by the reaction of iodine with glycogen.

In proliferating epithelium, the glycogen content is less because of increased keratinization, hence it is usually poorly stained or unstained with Lugol’s Iodine whereas the inflammatory tissues will stain dark brown because of increased glycogen content.

The system contains iodine, potassium iodide and distilled water. In the oral tissues, Lugol’s Iodine has less sensitivity in identifying oral premalignant and dysplastic diseases but is of greater specificity.

Tissue Reflectance

This category includes ViziLite ,ViziLite Plus and MicroLux DL. The ViziLite system and MicroLux are derived from an adjunct for diagnosing cervical lesions (speculoscopy). These products have been approved by the FDA to enhance the identification of oral mucosal lesions. For both systems, the patient is asked to rinse with a 1% acetic acid solution and then the oral cavity is examined by the clinician under the illumination of an activated chemiluminescent light (ViziLite) or a battery-operated light source (MicroLux DL). The 1% acetic acid wash is used to help remove surface debris and may increase the visibility of epithelial cell nuclei, possibly as a result of mild cellular dehydration.

The differentiation between normal and abnormal oral epithelium is based on color appearance under the blue-white light generated by those two light sources. The normal epithelium appears light bluish whereas the abnormal epithelium appears distinctly white (aceto-white). The ViziLite Plus also contains a tolonium chloride solution (TBlue) for marking the aceto-white lesion for subsequent biopsy once the light source is removed. Several studies have investigated the benefit of using the ViziLite compared to conventional visual examination alone. The ViziLite system was reported to highlight lesions of leukoplakia as well as oral benign lesions such as leukoedema, frictional keratosis, traumatic ulcer and lichen planus.

Most of these studies either did not include comparison to the diagnostic gold standard i.e. histopathologic diagnosis based on a scalpel biopsy, or contained only a limited number of cases subsequently biopsied, which made it difficult to assess specificity and sensitivity. There was only one study that correlated the ViziLite findings to the histopathologic diagnosis and the sensitivity, specificity and accuracy were reported to be 100%, 0% and 18.2%, respectively. Therefore, the system may provide little or very limited benefit over conventional visual examination in assessing clinically suspicious oral lesions.

Acridine binding method

In this method, the uptake of acriflavine by desquamated buccal cells is measured. Since the DNA content of the dysplastic cells are more, they will stain more intensely than normal cells.

PHOTODIAGNOSIS

This is referred to as Optoelectronics. It is based on fluorescence measurement. Light Induced Fluorescence (LIF) spectroscopy is useful for the early cancer detection in oral cavity. The principle of Light Induced Fluorescence (LIF) Spectroscopy technique is based on detection of endogenous tissue autofluorescence or exogenous fluorescence of photosensitizers selectively accumulated in tumor tissue. Photosensitizers which can be used are m-THPC or FOSCAN and delta aminolevulinic acid or LEVULAN. These include:

1. 5-Aminolevulinic Acid (ALA) Mediated Fluorescence Endoscopic Imaging.

2. 5-Aminolevulinic Acid Mediated Digitized Fluorescence Endoscopic Imaging.

3. Autofluorescence Spectroscopy.

4. Fluorescence Photography

5-ALA mediated fluorescence endoscopic imaging

Aminolevulinic acid is a precursor in biosynthesis of heme and it induces the production of endogenous photosensitizer protoporphyrin. After oral administration of ALA, synthesis of protoporphyrin occurs in dysplastic cells. This will result in fluorescence and can be easily detected. This may be a useful adjunct to pathological diagnosis, for directing biopsies and assessing resection margin for oral cavity lesions.

5-ALA mediated digitized fluorescence endoscopic imaging

It is the same method as above with digitalization facility. It has capability of high quality images and it can measure the fluorescence effect of diseased oral tissues.

Autofluorescence spectroscopy

This is a non invasive method, used for the detection of alteration in the structural and chemical composition of cells. This can be useful in guiding the clinician to the optimal location for biopsy. Autofluorescence occurs due to endogenous fluorophores. It consists of fluorophores from tissue matrix molecule, intercellular molecules like collagen, elastin and nicotinamide adenine dinucleotide phosphate.

Fluorescence Photography

The basic principle behind this is that, by repeated fluorescence photography, it will show reduction and diminution of positive fluorescence associated with cancer regression and vice versa. This is useful as an adjunct aid in the diagnosis of squamous cell carcinoma, although ultimately, biopsies are necessary.

MOLECULAR METHODS

In the development of neoplastic disease, progressive genotypic and phenotypic alterations such as the activation of protoncogenes and oncogenes and inactivation of tumor suppressor genes -associated with tumorigenesis- are detected in the affected cells, establishing the model of multistep tumorigenesis. It has been shown that identical mutations can be identified in bodily fluids draining a tumor, but, also lately in bodily fluids secreted away from the initial point where a solid tumor is developing. Nucleic acids and proteins related to cancer cells have been detected in plasma/serum, urine, saliva, bronchoalveolar lavage fluid, cerebrospinal fluid and other bodily fluids. These nucleic acids and proteins have been used as molecular markers for the early diagnosis of the disease, recurrence markers survival and metastasis predictors and decide the therapeutic approach.

Salivary markers

Saliva has been long proposed and used as a diagnostic medium because it is easily accessible and its collection is non-invasive, not time-consuming, inexpensive, requires minimal training and can be used for the mass screening of large population sample.

Molecular markers for the diagnosis of OSCC can be quested in 3 levels; (I) changes in the cellular DNA, which result in (II) altered mRNA transcripts, leading to (III) altered protein levels (intracellularly, on the cell surface or extracellularly). All these markers are summarized in Table

Changes in the Cellular DNA

Typical changes in the host DNA of dysplastic or cancer cells include point mutations, deletions, translocations, amplifications and methylations, cyclin D1, epidermal growth factor receptor (EGFR), microsatellite instability and HPV

Altered mRNA Transcripts

Various mRNA molecules were found up-regulated in the saliva of patients suffering from OSCC by the team of Li et al. Seven mRNA molecules were found significantly elevated in OSCC patients than in healthy controls.

1. IL8(interleukin 8) - playing a role in angiogenesis; replication; calcium-mediated signaling pathway; cell adhesion; chemo-taxis; cell cycle arrest; immune response,
2. IL1B which takes part in signal transduction; proliferation;inflammation and apoptosis
3. DUSP1 (dual specificity phosphatase 1) with a role in protein modification; signal transduction and oxidative stress,
4. H3F3A (H3 histone, family 3A) having a DNA binding activity
5. OAZ1 (ornithine decarboxylase antizyme 1) taking part in polyamine biosynthesis
6. S100P (S100 calcium binding protein P) with a role in protein binding and calcium ion binding, and
7. SAT (spermidine/spermine N1-acetyltransferase) which takes part in enzyme and transferase activity

Altered Protein Markers

Several salivary protein markers for OSCC have been investigated in various studies and have shown relatively moderate sensitivity and specificity values relative to prognosis prediction. For example, defensins are peptides which possess antimicrobial and cytotoxic properties. They are found in the azurophil granules of polymorphonuclear leukocytes. Elevated levels of salivary defensin-1 were found to be indicative for the presence of OSCC, since higher concentrations of salivary defensin-1 were detected in patients with OSCC compared with healthy controls.

Other salivary biomarkers which have been shown to be significantly altered in OSCC patients as compared with healthy controls are inhibitors of apoptosis (IAP), squamous cell carcinoma associated antigen (SCC-Ag), carcino- embryonic antigen (CEA), carcinoantigen (CA19-9), CA128, serum tumor marker (CA125), intermediate filament protein (Cyfra 21-1), tissue polypeptide specific antigen (TPS), reactive nitrogen species (RNS) and 8- OHdG DNA damage marker, lactate dehydrogenase (LDH) and immunoglobulin (IgG), s-IgA, insulin growth factor (IGF), metalloproteinases MMP-2 and MMP-11.

Molecular methods of oral cancer detection are:

1. Quantification of nuclear DNA content.

2. Tumor markers.

3. Micro satellite markers.

Quantification of nuclear DNA content

The DNA content of nucleus is dependent upon the number of chromosomes. In case of epithelial dysplasia and malignancy, there can be polyploidy (more number of chromosomes) or aneuploidy (abnormal number of chromosomes). So quantitative analysis of DNA content reflects the total chromosomal content which can be used to distinguish between malignant and normal cells. It is done by Flow Cytometer Analysis. Flow Cytometer is automated, precise, reproducible, reliable and objective measuring device of cellular DNA content. It scans only severe malignancy and has poor sensitivity.

Tumor markers

These are biochemical substances that can be hormones, enzymes or proteins that are produced and released by cancer cells or by host in response to cancerous substances. Tumor markers can be seen in blood circulation, body cavity fluids, cell membrane and cell cytoplasm. But in oral cavity, no markers are found in case of oral cancer. Tumor markers like PCNA,Ki-67 are found in some cases of leukoplakia. Besides, this method has poor sensitivity and poor specificity.

Microsatellite markers

It is one of the more sensitive techniques available for studying clonal changes in tumors and premalignant lesion. The advantage of this method is that only small quantities of DNA are required. It is done by Polymerase Chain Reaction based microsatellite analysis for allelic loss of genes that is seen in oral premalignant lesions.

IMMUNOFLUORESCENCE METHODS

These include:

1. Direct immunofluorescence

2. Indirect immunofluorescence

3. Sandwich technique of immunofluorescence

Fluorescent dyes such as fluorescin isothiocyanate(FITC) and rhodamine can be chemically linked (conjugated) with antibody globulin without destroying the specificity of the antibody. Such fluorescent labeled antibodies used to detect specific antigen-antibody reaction can be used to locate either antigens or antibodies of known specificity in tissue sections. When tissue sections labeled in this fashion are illuminated with UV light in a UV microscope, specific labeled tissue component can be identified by their bright apple green fluorescence against a dark or counter stained background. The technique is used to identify a number of tissue structures and abnormal deposits of antibody globulin and other macromolecules as well as bacteria and viruses in infected tissues and smears.

Direct immunofluorescence

Fluorescent labeled antiserum directed against a particular tissue component is applied directly to a thin, unfixed smear or tissue section mounted on a slide. The slide is then incubated at 370C to allow the antigen and the labeled antibody to react. Following incubation, the slide is washed in buffered normal saline to remove unreacted labeled antibody. The slide is examined under UV microscope.

Indirect immunofluorescence

Unlabeled specific antiserum is directed against a particular tissue component. This is applied directly to the smear or tissue section, allowed to react and followed by the application of a FITC conjugated anti-globulin antiserum. Following incubation and washing to remove the unreacted reagent, the slide is examined in the UV microscope. Here, the fluorescence is brighter because several fluorescent anti-globulin molecules bind onto each of the antibody molecules in the specific antiserum. Because the process of conjugation is lengthy, there is considerable cost saving and versatility to the indirect technique, which requires only one labeled antiserum. Staining of more than one tissue component per slide can also be accomplished.

Sandwich technique of immunofluorescence

The name ‘sandwich technique’ refers to the fact that antigen is sandwiched between two layers of the same specific antibody, one labeled and one not. Approximately fixed tissue sections are are reacted with a solution of the antigen for which specific antibody is to be identified in the section. Following incubation and washing, FITC labeled antiserum with the same specificity as that to be identified in the section, is applied to the section. The labeled antiserum again identifies the location of the tissue component.

HISTOPATHOLOGIC METHODS

These include:

1. Scalpel biopsy

2. Exfoliative Cytology.

3. Oral CDX Brush Biopsy.

4. FNAC.

Biopsy

It is a process of surgically removing tissue from a patient for histopathological examination. It is the removal of sample tissue from living tissue. It is the oldest method for the detection of oral cancer and also is the Gold Standard for the confirmatory diagnosis.

India is a poor man’s country and since cancer is a poor man’s disease, scalpel biopsy is the most preferable method for the detection of oral cancer because it is very cheap. Quick results can be obtained and can be done even in village settings, hence the most usual diagnostic test. Moreover, it is mandatory to do a scalpel biopsy for proper treatment, since it provides valuable information in determining the prognosis and type of treatment required.

Commonly used biopsies are excisional,incisional, punch, scrape and trephine. Some biopsy like bit, cone, core, endoscopic, irrigation, pressure, shave and sponge are less commonly used.

Excisional biopsy

Total excision of a small lesion for microscopic examination is called as ‘excisional biopsy’. It is a therapeutic as well as a diagnostic procedure. Normal tissue on the margins of the lesion should be included. It is the preferred treatment if the size of the lesion is such that it may be removed along with the margins of normal tissue and wound can be closed primarily. It is usually done in case of lesion smaller than 1cm. When the lesion is sessile or pedunculated, or when there is a movable tissue, excisional biopsy can be done.

For an excisional biopsy to be performed, aneasthetize the lesion with 2% local aneasthetic containing vasoconstrictor. Care is taken not to inject directly into the lesion that is to be removed. With the scalpel make an elliptical incision on either side of the base of the lesion so that the incision line is intersected. The blade should be at an angle of 450 towards the center of the lesion. Outward tension is placed on the lesion by means of suture or with the help of tissue forceps attached at the edge of the specimen. Care must be taken not to crush the specimen. The specimen is now gently dissected out with either a scalpel or a pair of surgical scissors. The tissue must be immediately submerged in 10% formalin. Surgical site is closed with either silk or absorbable sutures placed approximately 5mm apart.

Incisional biopsy

This can be performed by removing a wedge shaped specimen of the pathological tissue along with surrounding normal zone. If the lesion is large and diffuse and extends deeply into the surrounding tissue so that total removal cannot be obtained easily with local aneasthesia, an incisional biopsy is indicated. It is also done in lesions in which diagnosis will determine whether the treatment should be conservative or radical.

During an incisional biopsy, the selection of the site is very important. It is best to select the site away from an obvious ulceration or area of necrosis, as these are areas of intense inflammation which make interpretation difficult. The tissue around the specimen is infiltrated with 2% local aneasthetic. With a scalpel, make an elliptical incision encompassing the selected area of the lesion. The incisional lines must be deep enough to include underlying connective tissue to the level of muscle or bone. Suture is inserted through the end, upward tension is applied while tissue sample is dissected out.

Intraosseous biopsy

It is less frequently performed. It may be in the form of exploratory curettage in which the representative tissue is obtained to determine the nature of large radiological alterations.

After correlating the radiographs with overlying anatomical structures, the site of which the mucoperiosteal flap is to be raised is selected. Aneasthesia to the area is accomplished by block injection to the area and with local infiltration with a 2% local anaesthetic along with vasoconstrictor. With a scalpel, press firmly against the cortical bone, outline the flap using the periosteal elevator and strip the tissue from the bone. Using a small bone bur in low speed drill, make a small square window through cortical plate, along with a water spray as a coolant. Remove the cortical plate of bone and with curette, obtain deep sample of the underlying lesion and place the sample in 10% formalin. The surgical site is closed by replacing the flap.

Punch biopsy

It is rarely necessary in the oral cavity as most of the oral lesions are easily accessible. With this technique, the surgical defect that is produced is small and does not require suturing. In this technique, a sharpened hollow tube of several millimeters in diameter is rotated until underlying bone or muscle is reached. The tissue is then removed in the same manner as in incisional or excisional biopsy.

Frozen section biopsy

It is peformed inorder to get an immediate histological report of a lesion. It is done to determine whether a lesion is malignant or not. It is also used to evaluate the margins of an excised cancer, to ascertain that the entire lesion is removed at the time of surgery. The tissue is obtained from lesion and it is kept in deep freeze and then the frozen tissue is sectioned and stained to get a prompt diagnosis. In this type of biopsy, the slides cannot be preserved for future reference.

Exfoliative cytology

It is the microscopic examination of exfoliated cells from the epithelial surface. Here, the surface of the lesion is either wiped with some sponge material or scraped to make a smear. The appreciation of the fact that some cancer cells are so typical that they can be recognized individually has allowed the development of this technique, by Dr. George Papanicolaou, who is also known as the father of cytology and the technique is called as pap smear.

The principle is that cancer cells exfoliate more easily than normal cells mostly due to their lowered cohesiveness as a result of either decrease in number of tight junctions or lower calcium content. It is time saving, painless, cost effective and no aneasthesia is required. Extremely useful in the evaluation and diagnosis of uterine cervix cancer, but in the oral cavity, it gives rise to many false negative results. This is due to the increased thickness of oral epithelium where the malignant & premalignant cells are seen in the basal layer.

Oral CDX brush biopsy

The oral brush biopsy can be a fast, effective, and minimally invasive chair-side screening procedure. Oral CDx (Computer assisted brush biopsy) may bridge the gap between clinical inspection and histological evaluation of oral lesions with epithelial abnormalities. Any innocuous appearing oral epithelial abnormality may be initially screened for abnormalities with the oral brush biopsy technique, commercially marketed as the OralCDx kit (OralScanTM Laboratories Inc. Suffern, New York). Each kit contains all the materials and forms necessary to perform and submit the brush biopsy sample.

This technique requires the clinician to collect epithelial cells by rotating a provided circular brush against the lesion until pinpoint bleeding is seen clinically, indicating penetration of the basement membrane and a collection of cells from all layers of the epithelium. The biopsy brush was specifically designed to obtain a complete trans-epithelial biopsy and proper utilization of this instrument assures an adequate biopsy sample of all three epithelial layers (superficial, intermediate, and basal) of the lesion. All submissions are stained in accordance with a modified Papanicolau method and sent to the company for a computer-assisted specimen analysis. The stained slides are scanned by the OralCDx computer system specifically designed to detect oral epithelial precancerous and cancerous cells. The computer consists of neural network based image processing system specially designed to detect as few as two abnormal epithelial cells scattered among more than thousand cells on each biopsy specimen. The results are interpreted as falling into one of four categories: inadequate, negative, atypical, or positive; and the company recommend a follow-up scalpel biopsy for patients with an atypical or a positive result

Images of abnormal cells identified by the computer system are individually displayed on a high-resolution color video monitor for final review by a pathologist. It is a time consuming technique since in India there are only three centers (Delhi, Bombay, and Chennai) where brush biopsy specimens are processed. Also all positive cases should be confirmed by scalpel biopsy.

The brush biopsy technique is specifically marketed to screen those small non-suspicious mucosal lesions that are often trivialized or ignored. The technique is not intended to screen obviously suspicious lesions or to supersede clinical judgment in determining the need to biopsy. Advocates argue the technique has a positive predictive value of 30% to 38% (exceeding the Pap smear and mammography) and leads to earlier cancer diagnosis. Critics argue the technique yields an unacceptably high false positive rate, resulting in unwarranted patient anxiety and biopsy. Others note the possibility of obtaining a false negative report. While future studies are indicated to conclusively define the value of the technique, the authors contend the brush biopsy may serve as a bridge technique to assess the patient who may be hesitant to undergo a scalpel biopsy.

Fine needle aspiration cytology

It is the microscopic examination of an aspirate obtained by inserting a fine needle into the lesion. It is a painless and a safe procedure for rapid diagnosis. First discovered by Kun in 1847 and reintroduced in 1930 by Martin and Ellis. It is not a routine diagnostic test and is mostly indicated when the primary is not visible and a secondary node is present in the neck. It is also indicated in case of salivary gland pathology, as a replacement for extensive biopsy, in cases of recurrence and for the detection of metastatic squamous cell carcinoma within cervical nodes.

It is done using a 23gauge needle and a 5cc syringe. The needle should be first positioned within the target tissue and the plunger is pulled to apply negative pressure. Needle is moved back and forth within the target tissue to obtain a greater field. The negative pressure is then released while the needle remains within the target tissue. Needle is withdrawn and then the defumed air drawn in the syringe and the aspirate is blown onto the slide. Finally, fixing is done in absolute alcohol for 1 hour for pap stain and a little prolonged for HE stain.

NEWER METHODS

These include:

1. Tissue autofluorescence
2. In vivo confocal microscopy
3. Using Gold nanoparticles

Tissue autofluorescence

The study of autofluorescence in normal and abnormal oral tissues has been an ongoing research interest in various regions of the world for the past four decades and DeVeld et al. provide an excellent review. Tissue autofluorescence is produced by fluorophores that exist in living tissue upon excitation with a suitable wavelength. The fluorophores can be in the extracellular matrix (collagen and elastin), in the blood (hemoglobin) or in the cells (keratin, the reduced form of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD)). The concentration of fluorophores changes in pathological conditions that alter the blood concentration, nuclear size distribution, collagen content and epithelial thickness. Alterations in tissue autofluorescence have been observed in OSCC and in vivo autofluorescence imaging and spectroscopy have been applied for early detection of premalignant and malignant lesions in the oral cavity.

The VELscope is a hand-held device that was approved by FDA for the direct visualization of autofluorescence in the oral cavity. It was recently introduced to the market as a diagnostic adjunct for oral cancer detection. The VELscope consists of a light source which emits an intense excitation blue light (400-460 nm) and a handpiece with a selective filter for direct visualization. Under the illumination of this blue light, normal oral mucosa shows a pale green autofluorescence while abnormal tissue is proposed to show loss of autofluorescence and appears dark. The VELscope is a relative new device and so far only a limited number of studies have investigated its effectiveness as a diagnostic adjunct for oral cancer. The utilization of the VELscope as a general screening adjunct was also questioned since common oral inflammatory conditions, such as mucosal pigmentation, cheek biting, gingivitis, oral ulcerations and viral eruptions also frequently demonstrated loss of autofluorescence on VELscope examination.

In vivo confocal microscopy

Confocal microscopy is a well established imaging technique for research in cell biology. It provides the advantages of optical sectioning and high resolution imaging, achieved by blocking the light originating from tissue layers above and below the focal plane. Confocal microscopy was originally used for study ex vivo specimens but has been applied to in vivo human tissues in recent years. In vivo confocal reflectance microscopy has demonstrated the ability to obtain images of tissue architecture and cell morphology with resolution similar to histology. In addition, because of the optical sectioning ability of the instrument, no surgical procedure, sectioning or staining would be required for this procedure. In vivo confocal images have been successfully obtained from the oral cavity. A recent pilot study also showed that distinctive features such as nuclear irregularity and spacing in the images obtained by a fiber optic confocal reflectance microscope could be used to differentiate OSCC from normal oral mucosa. Although further optimization of the instrument and validation of the data is still needed, the promising results provide preliminary optimism for another non-invasive tool for the early detection of oral cancer and premalignant lesions.

Gold nanoparticles

The prefix of nanotechnology derives from ‘nanos’ the Greek word for dwarf. With the size of about one hundred to ten thousand times smaller than human cells, these nanoparticles can offer unprecedented interactions with biomolecules both on the surface of and inside the cells which may revolutionize cancer diagnosis and treatment. Various types nanoparticles include Quantum dots, carbon nanotubes, paramagnetic nanoparticles, liposomes and gold nanoparticles. Among all, gold nanoparticles being noble are nontoxic to human beings. There are many subtypes of gold nanoparticles like, gold nanospheres, nanorods, nanocages, SERS (surface enhanced raman scattering properties) nanoparticles and nanoshells. Many other types of gold nanoparticles with different size/shape, such as nanorods, nanoshells, and nanocages, have been explored to obtain optical properties suitable for biomedical applications. These metallic gold nanoparticles exhibit a unique optical response to resonantly scatter light when excited at their surface plasmon resonance frequency.

The epidermal growth factor receptor is a cell surface receptor biomarker that is over expressed in epithelial cancer but not in normal cells. The antiepidermal growth factor receptor antibody conjugated nanoparticles specifically and homogeneously bind to the surface of the cancer type cells with 600% greater affinity than to the noncancerous cells.

Raman spectroscopy is the most promising imaging technique for gold nanoparticles based contrast agents. Surface enhanced Raman scattering spectra of saliva from closely packed gold nanoparticles of normal cells and oral cancer cells were also differentiable . Thus, showed a promising result of using saliva as an assay for early diagnosis of oral cancer Gold nanoprobes that selectively and sensitively target tumor selective antigens were used to induce a distinct contrast in CT imaging in head and neck cancer. This showed that the attenuation coefficient for the molecularly targeted cells is over five times higher than for identical but untargeted cancer cells or normal cells. They used gold nanorods (AuNR) and conjugated them with UM-A9 antibodies which home specifically to squamous cell carcinoma of head and neck region for early detection of oral cancer2

Advantages of using gold nanoparticles for diagnosis is that it is simple, less invasive, provides increased contrast for diagnosis of oral cancer, is nontoxic to human beings, with no photobleaching or blinking which is inherent to many other fluorophores. Optical signal of gold nanoparticles may not be as strong as that of quantum dots, and other difficulties like biocompatibility, in vivo kinetics, tumor targeting efficacy, acute and chronic toxicity, and ability to escape the Reticuloendothelial system are the disadvantages.

CONCLUSION

Because the essence of malignancy escapes full understanding, prevention must be equated with early detection. The general dentist is clearly in a prime position to ensure early detection in the head and neck area. This is especially true for oral soft tissue lesions. The current standard of care for oral cancer assessment remains a comprehensive visual and tactile examination. Appropriate diagnostic procedures (e.g. biopsy) must be implemented as a matter of course in the evaluation of any lesion not responding to usual therapy in 7 to 14 days and when a malignancy is suspected. To safeguard and advance the welfare of the patient, whenever the diagnosis is in doubt, the clinician has the obligation to initiate consultation with or referral to a respected peer or specialist with special skills, knowledge, and experience.

6.Clinical Features of squamous cell carcinoma

Clinical features of Squamous Cell Carcinoma

The clinical features of oral squamous cell carcinoma are diverse and this disease can present in three major forms in different sites. There are three major types of presentation:

1. Exophytic growth
2. Painless indurated ulcers
3. Infilterating deep fissures

Carcinoma of the bucco gingival complex

There is considerable variation in the clinical appearance of carcinoma of buccal mucosa.The lesions develop most frequently along or inferior to a line opposite the plane of occlusion.The anteroposterior position is variable,some cases occurring near the third molar area,others forward toward the commissure

The lesion is often a painful ulcerative one in which induration and infileration of deeper tissues are common.Some cases,however,are superficial and appear to be growing outward from the surface rather than invading the tissues. Tumours of this latter type are sometimes called exophytic or verrucous growths

The incidence of metastases from the usual epidermoid carcinoma of the buccal mucosa varies considerably, but is relatively high. The most common sites of metastases are the submaxillary lymph nodes

It is generally agreed that carcinoma of the mandibular gingival is more common than that of the involvement of the maxillary gingiva.Carcinoma of the gingival is usually manifested initially as an area of ulceration which may be a purely erosive lesion or may exhibit an exophytic,granukar or verrucous type of growth.Many times, carcinoma of the gingiva does not have the clinical appearance of a malignant neoplasm.It may or may not be painful.The tumour arises more commonly in the edentulous areas,although it may develop in a site in which teeth are present.The fixed gingival is more frequently involved primarily than the free gingiva

The proximity of the underlying periosteum and bone usually invites early invasion to these structures.Although many cases exhibit irregular invasion and infilteration of the bone,superficial erosion arising apparently as a pressure phenomenon sometimes occurs.In the maxilla,gingival carcinoma often invades into the maxillary sinus,orit may extend into the palate or into the tonsilar pillar.In the mandible,extension into the floorof the mouth or laterally into the cheek as well as into the bone is rather common.Pathologic fracture sometimes occur in the latter instance.

Metastaseis is the common sequela of gingival carcinoma.Cancer of the mandibular gingiva metastasizes more frequently than cancer of the maxillary gingival.In most series of cases,metastasis to either the submaxillary or the cervical nodes eventually occur in over 50% of the patients regardless of whether the involvement is maxillary or mandibular.Spread to the jaw bones through periodontal space is reported.

Carcinoma of the Tongue

In the West, it is the most common oral carcinoma with 60% cases arising from the anterior two-third of the tongue and remainder from the base.Carcinoma of the tongue is caused by physical trauma,alcohol,tobacco smoke,caddidiasis,syphilis,sepsis,chronic dental trauma and chronic superficial glossitis

Clinical Features

Age and sex-Carcinoma of the tongue is disease of middle and later decades of life,with mean age of presentation being about 60 years.Males are more commonly affected than females

Site-The majority of tongue carcinoma occurs on lateral border of anterior two-third of the tongue and under surface of the tongue.The lesions on the posterior border of the tongue are usually of higher grade malignancy metastasize earlier and often have a poor prognosis.Cancers located in the anterior two-third of the tongue are detected in early stages,as compared to those in the posterior one-third of the tongue

Painless mass or ulcer-The most presenting signs of carcinoma of tongue is a painless mass or ulcer,although in most patients the lesion becomes painful, especially when it becomes secondarily infected.

Salivation-Excessive salivation gradually appears along with the growth.In later stages,saliva becomes blood stained

Foetor oris-As the patient is unable to swallow saliva,offensive smell in the mouth occurs due to infections by gram negative bacteria

Sore throat-There is complaint of sore throat and pain in case of lesions on posterior border of the tongue

Immobilty of the tongue-It occurs due to extensive carcinomatous infiltration to the lingual musculature.It becomes worse when floor of mouth is involved and ultimately,it causes difficulty in speech

Hoarseness of voice and dysphagia-It is present when the carcinoma involves posterior third with the involvement of pharynx and larynx

Signs-Carcinoma of the tongue may be seen in two varieties

Ulcerative growth-It is usually seen near the edge of the tongue.The ulcer looks irregular and the edges are raised and everted.The floor is covered by yellowish gray slough.Base is indurated

Warty growth-It usually possesses a broad and indurated base.It is developed on excess proliferating growth of filiform papillae.Rarely,it takes cauliflower type of growth

Progress-The tumour may begin as a superficiallyindurated ulcer with a slightly raised border and may proceed either to develop a fumigating,exophytic mass or to infilterate the deep layers of tongue,producing fixation and nduration without much surface changes.At an early stage, tongue cancer may appear as thickened,leukoplakic patches or as a nodule

Complication-Patient usually diees due to cancerous.Cachexia,starvation,inhalation bronchopneumonia,asphyxias and haemorrhage involved from cervical lymph nodes

Spread of Carcinoma

Local spread-It spreads by infilteration and invasion

Carcinoma of anterior two-third of the tongue-It usually starts on the lateral margins of the tongue and invades the floor of the mouth early,but it does not extend to the other side across the midline

Carcinoma of the posterior one-third of the tongue-It tends to spread to the corresponding tonsils,epiglottis and soft palate

Lymphatic spread

Tip of the tongue-Carcinoma of tip of the tongue may drain to the submental nodes,but may also drain to the juguloomohyoid nodes

Anterior two-third-It drains into the submandibular lymph nodes

Posterior one-third-It drains into jugulodigastric group of the deep cervical nodes on both sides of the neck

Blood-It is rare and extremely late in occurrence.It is only seen when the growth is in extreme posterior part of the tongue

Carcinoma of the Lip

There is considerable variation in the appearance of lip cancer,depending chiefly upon the duration of the lesion and the nature of the growth.The tumour usually begins on the vermillion border of the lip to one side of the midline. It commences as a small area of thickening, induration and irregularity of the surface.As the lesion becomes larger,it may create a small crater like defect or produce an exophytic,proliferating growth of tumour tissue.Some patients have large fungating masses in a relatively short time.While in other patients,the lesion may be only slowly progressive

Carcinoma of thelip is generally slow metastatize and a massive lesion may develop before there is evidence of regional lymph node involvement.Some lesions,however,particularly the more anaplastic ones,may metastasize early.When metastasis does occur,it is usually ipsilateral and involves the submental or submaxillary nodes.Contralateral metastasis may occur,especially if the lesion is near the midline of the lip where there is a cross drainage of the lymphatic vessels

Carcinoma of the floor of the Mouth

Carcinoma of the floor of the mouth represents approximately 15% of all cases.

Clinical Features

The typical carcinoma in the floor of the floor of the mouth is an indurated ulcer of varying size situated on one side of the midline.It may or may not be painful.This neoplasm occurs far more frequently in the anterior portion of the floor than in the posterior area.Because of its location,early extension into the lingual mucosa of the mandible and the mandible proper as well as into the tongue occurs with considerable frequency.Carcinoma of the floor of the mouth may invade the deeper tissues and may extend into the submaxillary and sublingual glands.The proximity of this tumour to the tongue,producing some limitation of motion of that organ,often induces a peculiar thickening or slurring of speech

Metastases from the floor of the mouth are found most commonly in the submaxillary group of lymph nodes and since the primary lesion frequently occurs near the midline where a lymphatic cross drainage exists,contralateral to metastasis are present

Carcinoma of the palate

Palatal cancer usually manifests itself as a poorly defined,ulcerated,painful lesion on one side of the midline.It frequently crosses the midline,however,and may extend laterally to include the lingual gingival or posteriorly to involve the tonsilar pillar or even the uvula.The tumour on the hard palate may invade into the bone or occasionally into the nasal cavity ,while infiltrating lesions of the soft palate may extend into the nasopharynx

The epidermoid carcinoma is almost invariably an ulcerated lesion whereas the tumors of accessory salivary glands origin,even the malignant lesions,are often not ulcerated, but are covered with an intact mucosa.This fact may be of some aid in heping to distinguish cloinically between these two neoplasms.

Metastasis to the regional lymph nodes occur in a considerable percentage of cases,but there is little evidence to indicate whether such metastases are more common in carcinoma of the soft palate or in that or hard palate

TNM classification of Lip and Oral cavity carcinomas

Rules for classification

The classification applies only to carcinomas of the vermillion surfaces of the lips and of oral cavity,including those of minor salivary glands.There should be histological confirmation of the disease.The following are the procedure for the assessment of the T,N&M categories

T category:Physical examination & imaging

N category:Physical examination & imaging

N category:Physical examination & imaging

M category:Physical examination & imaging

Anatomical sites and subsites

Lip(ICD Coding)

1. External upper lip(vermilion border)(C00.0)

2. External lower lip(vermilion border)(C00.1)

3. Commissures(C00.6)

Oral cavity

1. Buccal mucosa

- Mucosa of upper and lower lip(C00.3,4)

- Cheek mucosa(C06.0)

- Retromolar areas(C06.2)

- Buccoalveolar sulci,upper & lower(vestibule of the mouth)(C06.1)

2. Upper alveolus and gingival(upper gum)(C03.0)

3. Lower alveolus and gingival(upper gum)(C03.1)

4. Hard palate(C05.0)

5. Tongue

- Dorsal surface & lateral borders anterior to vallate papillae(anterior two-thirds)(C02.0,1)

- Inferior(ventral)surface(C02.2)

6.Floor of mouth(C04)

Primary Tumor (T)

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ

T1 Tumor 2 cm or less in greatest dimension

T2 Tumor more than 2 cm but not more than 4 cm in greatest

dimension

T3 Tumor more than 4 cm in greatest dimension

T4 (lip) Tumor invades adjacent structures (e.g., through

cortical bone, tongue, skin of neck)

T4 (oral cavity) Tumor invades adjacent structures (e.g.,

through cortical bone, into deep [extrinsic] muscle of

tongue, maxillary sinus, skin)

Regional Lymph Nodes (N)

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greater dimension

N2 Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N2a Metastasis in single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension

N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension

N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N3 Metastasis in a lymph node more than 6 cm in greater dimension

Distant Metastasis (M)

MX Presence of distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis

Table 5: TNM Clinical Stage Grouping 16

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While referring a patient to the cancer treatment centre,it will be better to put the TNM& Staging in the referral letter

Verrucous Carcinoma

Verrucous carcinoma also known as Ackermann carcinoma was first reported by Ackermann in 1948. It is a warty variant of squamous cell carcinoma characterised by a predominantly exophytic overgrowth of well differentiated keratinizing epithelium, having minimal atypia, and with locally destructive pushing margins at its interface with underlying connective tissue. The invading margin is usually below the level of surrounding mucosa. The advancing epithelial border is broad and the basement membrane is generally intact. There is usually a heavy inflammatory cell reaction in the adjacent connective tissue. Growth is generally slow and metastatic spread occurs late. These carcinoma becomes aggressive if irradiated. Occasionally, foci of squamous cell carcinoma may occur with a verrucous carcinoma, so thorough sectioning of specimen is necessary.

Clinical features:

Verrucous carcinoma is generally seen in elderly male patients; mean age of occurrence being 60-70 years. Though majority of cases occur on buccal mucosa and gingival/alveolar ridge; palate and floor of mouth are also occasionally involved. The neoplasm in early stage appear as white keratotic patch and in later stage is chiefly exophytic and appears papillary in nature with a pebbly surface. White leukoplakic film may sometimes be seen covering these surfaces. The lesion commonly have rugae like folds with deep clefts between them. Lesions of the buccal mucosa may become quite extensive before the involvement of deeper contiguous structures, where as those of mandibular ridge or gingiva rapidly become fixed to the periosteum,gradually invading and destroying the mandible. Regional lymph nodes are often tender and enlarged due to inflammation. Patient usually presents with pain and difficulty in mastication and rarely bleeding. There is definite association with tobacco use, including smoking, snuff dipping, and betel chewing. The tumor is most frequently preceded by leukoplakia, which was noted in upto 57% patient in one series. It may also be preceded by oral lichenplanus, chronic candidiasis and chronic lupus erythematosis.

Spindle cell carcinoma

Males are commonly affected, with mean age of 57 years. Lower lip, tongue and alveolar ridge are most commonly affected. Swelling, pain, and presence of a non healing ulcer are the most common presenting complaints. Initial lesion may be with a polypoid, exophytic or endophytic configuration

Adenoid squamous cell carcinoma

Commonly affects skin and rarely lips are also affected. Lip lesions often appear clinically similar to epidermoid carcinoma, ulcerated, hyperkeratotic, or exophytic. Intraorally lesions have been reported on tongue and gingiva.

7 (a)Radiotherapy in Oral Cancer

DEFINITION

Radiotherapy or Radiation Therapy is the treatment of diseases using ionizing radiation. For therapy high-energy radiation in megavoltage range is preferred where as for diagnosis kilo voltage energy is used.

PRINCIPLES OF RADIOTHERAPY (RT)

The radiotherapy is based on the basic principle that rapidly proliferating cells are more sensitive to ionizing radiation compared to normal cell. This differential cell kill is used for the treatment of tumors.

PHYSICAL CONCEPTS IN RADIATION ONCOLOGY

Ionizing radiation used to treat cancers is divided into electromagnetic radiation and particle radiation. Electromagnetic radiation is the predominant therapeutic modality for radiation therapy. The electromagnetic spectrum ranges from low energy to higher energy. This includes megavoltage radiations such as gamma rays and megavoltage X-rays. Particle radiations include electrons, neutrons and protons.

X-rays and gamma rays are essentially the same type of electromagnetic radiation (photon). They differ in the ways they are produced. X-ray are produced by man made devices by introducing a target material along the pathway of fast moving electrons. Gamma rays are emitted from a radioactive isotope as part of the process of naturally occurring radioactive decay. RT with particle radiation differs from photon radiotherapy in that it involves the use of fast-moving subatomic particles to treat localized cancers. Most particles (neutrons, protons etc) deposit more energy while passing through tissues, thus causing more damage to the cells they hit. Recent advance in radiotherapy research is the use of radiolabeled antibodies to deliver doses of radiation directly to the cancer site (radioimmunotherapy). Tumor-specific antibodies against tumour antigens labeled with radioactive isotopes (radiolabeling) are injected into the body, which actively seek out the cancer cells and destroy them by the cytotoxic action of the radiation. This approach can minimize the risk of radiation damage to healthy cells.

METHODS OF DELIVERY OF RADIOTHERAPY

Based on the method of delivery radiotherapy treatment is classified into teletherapy, brachytherapy and internal therapy.

Teletherapy

Radiation given using machines kept at a distance away from the patient. Based on the energy this is subdivided into:

a. Superficial Therapy

Superficial voltage machine generate X-rays 30-125 KV. This is used to treat superficial tumors like skin cancer.

b. Orthovoltage Therapy (Kilovoltage)

Orthovoltage machines produce medium energy X-rays in the range of 200-300 kv. Primarily used to treat superficially situated tumors. In this situation skin dose is high and cannot be used to treat deep seated tumors.

c. Megavoltage Therapy

Megavoltage machines such as telecobalt and linear acceleraters generate radiations having energy above one megavoltage. These machines are used to treat deeply situated tumors delivering lesser dose to the overlying skin.

Telecobalt Teletherapy (Co 60)

In telecobalt machine radioactive isotope (Co 60) which emit gamma rays having an average energy of 1.25 MeV.

Linear Accelerator

These are the most commonly used radiotherapy machines. This does not contain a continuously emitting radioactive isotope. In this machine electrons are generated, accelerated and made to strike a target to produce high voltage X rays. The advantage of this machine is that both X rays and electrons can be utilised for treatment. Electrons are commonly used to treat superficial tumors without damaging underlying critical structures.

Brachytherapy

Radiation source is kept in close contact or with in the tumour. The commonly used isotopes are Radium 226, Cesium 137, Iridium192 and Iodine125. The treatment usually lasts for few days.

Brachytherapy is often divided into three types:

a. Intracavitary brachytherapy: Radioactive isotopes are kept inside a body cavity, e.g. carcinoma of nasopharynx

b. Interstitial brachytherapy: Radioactive isotopes are implanted into the tumor, e.g. Carcinoma tongue and buccal mucosa

c. Mould therapy: Radioactive isotopes are kept in close contact with the tumor, e.g. carcinoma of hard palate and skin cancer

Interstitial and mould therapies are commonly used for the management of oral cancer. This is used as a boost following external Radiotherapy or as a single modality in early stage disease.

Internal Therapy

Radioisotope is either injected or taken as a drink to treat tumors. For example: Radioactive iodine (I131 ) in the treatment of thyroid cancer.

Phosphorus -32 in the treatment of polycythemia vera.

External BEAM Radiotherapy (teleTHERAPY)

External radiotherapy is normally given as a series of short daily treatments, usually from Monday through Friday, in the radiotherapy department using teletherapy machine (telecobalt / linear accelerator). While taking treatment patient will be alone in the treatment room. However he will be closely monitored through a closed circuit camera. The patient can have normal social life and there won’t be any radiation emitted from the patient.

FRACTIONATION IN RADIOTHERAPY

Fractionation is a term used to describe the manner in which daily dose of radiation is given. Fractionation of the total dose of radiation helps in minimizing normal tissue reaction. The clinical effects of fractionated radiotherapy are influenced by the ability to repair sublethal damage, reoxygenation of tumour during the course of radiation, repopulation of tumour and normal tissues between fractions and redistribution of cells into a more sensitive phase in cell cycle treatment. (The 4 R’s of radiobiology).

CONVENTIONAL FRACTIONATION

Conventional fractionation is the application of daily doses of 180-200 cGy and 5 fractions per week to a total dose of 40-70 Gy depending upon the type of tumor.

HYPERFRACTIONATION

Two or more fractions per day of reduced dose (115-120 cGy) with overall treatment time similar to that of conventional fractionation. Hyperfractionation helps in increasing the total dose without increasing the late reactions.

ACCELERATED FRACTIONATION

Accelerated fractionation is a means of decreasing the overall duration of treatment in an effort to reduce the repopulation of tumour cells in rapidly proliferating cancers. Repopulation (tumour –cell regeneration)occur during treatment when the overall duration of treatment is increased. Shortening of overall treatment time can increase the tumour control in selected situation.

ACCELERATED HYPERFRACTIONATION

Delivering two or more fractions per day of normal dose per fraction helps in reducing overall treatment time without increasing the risk of late complication.

Concomitant-boost Technique

A variant of accelerated fractionation is the concomitant boost technique. With this technique, treatment is delivered once daily for the first 3.5 weeks and then twice daily during the final 2 to 2.5 weeks, when tumour cells can begin to repopulate more rapidly.

Hypofractionation

Here less than four fractions per week with higher dose per fraction than conventional is planned. In selected situations this is found to be useful especially in the treatment of melanomas.

Split Course Therapy

Radiation is given in small courses with a rest period in between.

SIDE EFFECTS OF RADIATION In Head and Neck Cancer patients

Radiotherapy side effects are classified into acute and late.

Acute Reaction

Acute reaction occurs during and immediately after treatment upto 6 weeks. Acute effects are related to dose per treatment, total dose, volume of tissue irradiated and the site. These reactions are limited to the area irradiated and not seen outside the treatment volume. This is mainly due to the inflammation of the tissues during treatment. Symptoms include xerostomia, pain in the mouth and throat, skin reactions and falling of hair within the treatment volume may occur The mucous membrane with in the irradiated area gets inflamed leading to patchy ulceration. During therapy salivary secretion decreases and it become thicker and forms a coating over the tongue. This cause change in the pH of the saliva, which can lead to changes in the bacteria flora. During radiotherapy there will be alteration of taste.

These acute reactions are self limiting and usually subsides in 2-3 weeks following completion of radiotherapy. There can be superadded bacterial and fungal infections. This is managed by antibiotic, antifungal and analgesics. During therapy patients are advised to take high calorie non-spicy bland food. Frequent use of soda bicarbonate and saline mouthwash is advisable. They should not use very hot and very cold food during treatment. During treatment patient should avoid application of creams and oils and rubbing of the skin with rough clothes should be avoided.

Late Reaction

This is the dose limiting toxicity and usually occurs months or years after treatment. This depends upon the dose per fraction, total dose and volume of tissue irradiated. This includes dryness of mouth, intolerance to spicy food, hair loss and oedema of the skin with in the irradiated area. Necrosis, fistula formation, non-healing ulceration and osteonecrosis are rare. However modern radiotherapy delivery is very precise and accurate and damage to critical structures are extremely rare.

ADVANTAGES OF RADIOTHERAPY

- No tissue or functional loss

- Good cosmetic outcome compared to surgery Control of subclinical disease in the regional nodes is possible without added morbidity

- Can simultaneously treat multiple primaries.

- Better surgical salvage of radiotherapy failures than radiotherapy salvage of surgical failures.

- Rare treatment related mortality

DISADVANTAGES OF RADIOTHERAPY

- Undesirable acute side effects such as painful mucositis, loss of taste, dryness of mouth etc.

- Potential late complications of soft tissues and bone

- Protracted treatment course

- Requires good infrastructures

- Rare possibility of development of second malignancy

Principles of Radiotherapy in ORAL Cancer

The use of radiation therapy in the management of oral cancer is based on the following principles.3

1. Squamous cell carcinoma is generally radioresponsive and in early stage highly radiocurable.

2. The more differentiated the tumor the less rapid the radiation response and resolution and the higher the radiation dose required.

3. Exophytic and well oxygenated tumors are more radioresponsive than deeply ulcerative and infiltrative hypoxic tumors.

4. Squamous cell carcinoma, when limited to the mucosa are highly radio-curable.

5. Bone and muscle involvement by carcinoma adversely alters radioresponsiveness and subsequently decrease radiocurability.

6. The early small metastases can be controlled with radiation therapy alone. Advanced cervical metastatic lymph nodes are better treated with combined surgery and RT.

Indications of RT

1. T1-T2 lesions as single modality

2. T3 - T4 locally-advanced lesions

Combined surgery and radiotherapy or combination of chemoradiotherapy

Combined Surgery and Radiotherapy

Radiotherapy can be given before or after surgery. Each sequence has theoretical advantages and disadvantages.

However, the results from randomized studies favor post­operative radiotherapy.4-5 In practice, most surgeons also prefer to operate in an unirradiated field where frozen section control of resection margin can be obtained. In certain clinical settings, however, planned preoperative radiotherapy may be favoured. These include situations where cancer is not respectable at presentation or when a free osteomyocutaneous graft is to be used for mandibular soft tissue reconstruction. In the latter situation avoidance of irradiating the graft and delivery of a lower dose to the mandibular stump than would be necessary in post­operative setting both facilitate integration of the vascular graft.

Indications for Postoperative Radiotherapy

- Positive resected margins
- Locally-advanced primary regardless of margin
- Multiple involved nodes
- Extra capsular extension
- Perineural spread
- Vascular and lymphatic emboli

Timing of Radiation

The general guideline is to commence radiotherapy when tissues are well healed. Radiotehrapy should be started as early as possible after proper wound healing preferably within 6 weeks. The longer the interval before the commencement of radiation, the greater the opportunity for presumed clonogens to proliferate. A delay of more than 6 weeks can adversely affect the outcome.6

Combined Chemotherapy and Radiotherapy Treatment

Chemotherapy is generally used along with radiation in organ conservation settings, especially in locally advanced tumours to avoid surgery. Chemotherapy can be combined with radiotherapy-in various ways.7

Neoadjuvant /Anterior / lnduction Chemotherapy

Chemotherapy is given before local treatment like radio­therapy and surgery. This has 2 percent survival benefit.

Concurrent Or Concomitant Chemotherapy

Chemotherapy is given along with RT. This has 8 percent survival benefit.

Adjuvant Chemotherapy

Chemotherapy is given after local form of treatment like radiotherapy or surgery. This has one percent survival benefit.

Table.2: Survival rates in oral cancer

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REFERENCES

1. Dru forrester S. Principles of cancer management part ii. Surgery, radiotherapy, hyperthermia, immunotherapy, 1997.

2. Baumann M, Saunders M, Joiner MC. Modified Fractionation in Basic Clinical Radiobiology. Ed. Steel G G, 2002;147.

3. Wang CC. Radiation Therapy for Head and Neck neoplasms: Indications, Techniques and Results. 2nd Ed.1990

4. Kramer S, Gelber RD, Snow JB et al. Combined radiation therapy and surgery in the management of advanced head and neck cancer: final report of study 73-03 of the RTOG. Head and Neck Surgery 1987; 10: 19-30.

5. Vandenbrouk C, Sancho H, Le Fur R et al. Results of a randomized clinical trial of preoperative irradiation versus postoperative in treatment of tumors of the hypopharynx.Cancer 1977; 39: 1445-49.

6. Peters LJ, Goepfert H, Ang KK et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Biol Phys 1993; 26: 3-11

7. Bourhis J, Pignon J P. Metaanalysis in head an necksquamous cell carcinomas. What is the role of chemo­therapy? Hemat Oncol Clin North Am, 1999;13:769-75.

7(b).Surgical management of oral cancer

HISTORICAL PERSPERCTIVES

The earliest known procedures regarding cancer surgery was mentioned by Sushruta, a member of caste of porters in his book sushruta smahita about 600BC.In his book he has mentioned about the existence of tumour and its metastasis growth. He designed many surgical instruments for his surgery. He transposed skin from forehead and cheek to reconstruct nose and lips. Even he has defined cancer in his book.

SURGICAL PLANNING & ASSESSMENT

The surgeons goal is complete removal of primary tumor and of any involved regional lymph nodes while preserving the integrity of uninvolved structures.

Surgical planning and execution requires an indepth knowledge of the surgical anatomy and physiological function of surgical field. The ablative surgery of oral cancer must be designed and executed to remove the malignant tissues enbloc with a margin of normal tissue .small anteriorly situated tumors can be excised per orally with clear margins.

The oral cavity is divided in to the following subsites :-

The lip , anterior two-thirds of the tongue, floor of the mouth, gingiva , retromolar trigone, buccal mucosa & hard palate. The site information is important , because tumours of different subsites demonstrate distinct biology in terms of the tendency for local invasion, their metastatic potential and their sensitivity to treatment modalities.

The assessment of patients with oral carcinoma consists of patients history, physical examination augmented by histopathological tissue diagnosis and image and metastatic workup which includes TNM classification and state grouping

TONGUE

Anterior 2\3rd of the tongue is the most common site of primary lesions accounting for 40% of oral cancer . Most malignancies occur in the lateral border and ventral surfaces of tongue , but occasionally confined to tip & dorsum.

Tongue cancer may spread along the mucosal surface to involve the floor of the mouth, mandible or oropharynx .It also cause deep invasion of the tongue musculature , which provides a pathway for invasion without fascial barriers .The surgical protocol includes wide resection of tongue cancer with 1 to 1.5cm of normal tissue to ensure adequate excision .The margins are assessed by fresh frozen section intraoperatively to rule out close margins.

The potency to metastasis is related to the “T”stage and the depth of invasion of tongue cancer. Depending on the “T” stage and depth of the lesion an elective supra omohyoid neck dissection (SOHND) is done for the lymph node metastasis

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BUCCAL MUCOSA

This area includes the epithelial lining of the inner surface of the lips and the oral surface of the cheeks to the line of attachment of mucosa superiorly and inferiorly at the alveolar ridge of the upper and lower jaws .Its posterior limit is the attachment at the retromolar trigone.

Carcinoma of the buccal mucosa are usually squamous carcinoma frequently associated with areas of leukoplakia .Growth patterns may be verrucous, exophytic or ulcerative .Common sites are in mid and posterior part of cheek along the white line .Advanced lesion may perforate the skin of cheek.

Buccal mucosal lesions shows lymph node metastasis involving level I to level IV.

Treatment options include wide excision of lesion with clear margins of involved buccal mucosa and skin.

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FLOOR OF THE MOUTH

Floor of the mouth is the subsite of 25% of oral cancers. The frequency may be due to dependent location and pooling of saliva in this area. Floor of the mouth lesions extent to involve tongue , mandibular gingiva and mandible. The lesions proximity to the mandible determines the surgical planning of the mandibular recession as well .

Floor of the mouth cancers require extended recessions including parts of the tongue or segmental mandibular recession via lip splitting incision, transoral approach . Elective supraomohyoid neck dissection (SOHND) is appropriate for T1 lesions of floor of the mouth & bilateral neck dissection is indicated for midline lesions

Maxillary alveolar ridge and Hard palate

Carcinomas of hard plate and upper alveolus are relatively uncommon & accounts10% of oral cancers. These areas are lined with adherent keratinized mucosa which provides protection from force of mastication. Common carcinoma affecting these areas are squamous cell carcinoma ,minor salivary gland carcinomas and kaposi sarcomas. Metastatic rate is less.

Surgery is the treatment of choice for maxillary alveolar and hard palate .It is necessary to resect periosteum and bone to ensure an adequate clear margin of 1cm of minimal clear margin necessary around the lesion. Depending upon the T stage, partial or subtotal maxillectomy is preferred with Weber Fergusson approach.

Surgical management of neck in oral cancer

Cancer of oral cavity has a distinct predilection for lymphatic spread before distant systemic metastasis. The survival of oral cancer patients is reduced by 50% when metastatic disease in the neck is present at the time of diagnosis.

A thorough understanding of lymphatic anatomy of the neck and biology of nodal metastasis is very important in treating the neck .Lymph nodes serve as a source for immunologic cells and provide immunologic function in head and neck. Malignant cells from primary tumor are carried in the lymph nodes by a flow of extracellular fluid through the lymphatic channels. The lymph nodes is favorable for proliferation of metastatic squamous cells and the resulting tumors destruct the architecture and functions of node , eventually violating the lymph node capsule leading extracapsular spread. Finally systemic metastatic spread of disease occurs. The tumors of tongue have the highest incidence of neck metastasis of all oral subsites. In decreasing order of frequency of metastasis, the other subsites are the floor of the mouth , buccal mucosa ,hard palate and lips.

Surgical Treatment

The surgical procedure involves either comprehensive (removing all five nodal levels) or selective (removing less than five levels) neck dissection .The classical radical neck dissection, successfully done by GEORGE W. CRILE advocated removal of nodes of all five levels plus the sternocleidomastoid muscle ,internal jugular vein and spinal accessory nerve.

Comprehensive dissections that preserve one or more of the non lymphatic structures removed during radical neck dissection are termed modified radical neck dissection, of which there are three types:-

Type 1- which preserves only the spinal accessory nerve

Type2-which preserves two structures the spinal accessory nerve and either the sternocleidomastoid muscle or the internal jugular vein

Type 3-which preserves all the three structures.

Selective neck dissection preserve the sternocleidomastoid muscle , the internal jugular vein and the spinal accessory nerve and remove less than five levels of lymph nodes. Common selective neck dissection involves SOHND or jugular neck dissection

Hemimandibulectomy

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Reconstruction of Maxillofacial Defects

Reconstruction following ablative oncology surgery will depend on numerous factors includes site, size , composition of the defect ranging from simplest to complex , to achieve the greatest functional and aesthetic defects with least morbidity.

Carcinoma tongue, reconstruction with submental flap

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\

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Forehead flap for cheek reconstruction

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Local flaps for reconstruction

1. Buccal fat pad

2. Nasolabial flap

3. Tongueflap anteriorly and posteriorly based

Axial pattern flaps (Fascio cutaneous flap , fascial flaps)

1. Sub mental

2. Temporo parietal

3. Deltopectoral

Muscle, Myocutaneous flaps

1. Platysma

2. Pectoralis major

3. Infra hyoid

4. Masseter

5. Temporalis

6. Trapezieous

Deltopectoral flap

Abbildung in dieser Leseprobe nicht enthalten

The development of micro vascular surgery and free tissue transfer has revolutionized reconstruction.

Common free vascularised flaps are

1. Radical forearm flap

2. Rectusabdominus muscle flap

3. Latysmus dorsi flap

4. Free fibula flap

The availability of forehead , temporalis and deltopectoral flaps changed the approach to head and neck cancer surgery with new emphasis on immediate reconstruction. The surgeon may choose the transposition flap, microsurgical transplantation ,or tissue expansion with the goals of achieving form & function at the recipient site , avoiding donor site deformity , providing safety throughout the reconstructive procedure.

CONCLUSION

A thorough understanding of cancer biology,diagnosis, planning and protocol is necessary for the management of oral cancer. Precancer evaluation and councelling , surgery, radiotherapy, chemotherapy and palliative care works hand in hand for effective cure for oral cancer patients.

Leisure use of tobacco in various forms leads to such harmful effects on humans.

KINDLY AVOID IT

8. Management of complications associated with the treatment of oral cancer.

Patients with oral and oropharyngeal cancer often contend with severe pain, anatomic and esthetic defects after treatment. These problems may be related to surgical treatment of the primary tumour or neck, radiation treatment of the 1° tumour or neck, or chemotherapy . The size and location of the 1° tumour and the presence or absence of disease in the neck also have a major impact on morbidity.

Complication associated with radiation treatment for head and neck cancer

- oral mucositis
- xerostomia
- loss of taste
- mucosal pallor
- gingival bleeding
- radition caries
- osteoradionecrosis
- endocrine abnormalities

Complications associated with surgical treatment of the primary tumour

- Speech defects
- swallowing defects
- neurological dysfunction
- wound break down and fistula formation

Complication associated with surgical treatment of the neck

- shoulder dysfunction and pain
- cranial nerve injury

miscellaneous

- radiation neuritis
- trismus
- visual impairment
- pain
- dentofacial abnormalities

Complications associated with surgical treatment of primary tumour

Patient with oral & oropharyngeal cancer often manifest severe functional, anatomic and esthetic problems after treatment. Because the size and location of the primary tumour dictate the extent of resection, the sacrifice of important contiguous structure is often mandated by the disease and the principles of oncologic safety. Loss of tongue and floor of mouth musculature, removal of bone and associated muscle attachments, and the sacrifice of both sensory and motor cranial nerve greatly affect aesthetic, speech swallowing and nutritional status as well as psychosocial function. The use of bulky & dynamic distal flaps for immediate reconstruction can further result in problems, especially articulation and oral phase of swallowing. Scar contracture, of both the skin and the muscles of mastication, creates additional problem with mobility and resultant trismus.

Speech deficits

Various measures of speech intelligibility have been utilized in post operative oral cancer patients to better appreciate the defects associated with tongue and floor of mouth resections. The speech defects associated with tongue and floor of mouth resections. The speech deficit was found to correlate with the amount of tongue resected as well as removal of tongue substance from posterior third.

The major facial consideration with tongue resection is the resultant decrease in mobility. Glossectomies may be closed primarily, left to granulate secondarily skin grafted , or closed with local flaps , regional pedicled flaps, or free flaps. These decisions are based on size of ablative defect and the need for additional soft tissue. In case of partial glossectomy involving the anterior 2/3rd of tongue, 1° closure. Often result in the least functional involvement. With greater than ½ of the anterior 2/3rds of tongue removed, a skin graft or flap may be indicated , especially when the anterior floor of mouth is also resected. Tongue base resection that interfere with the tongue-palatal contact may lead to nasopharyngeal incompetence , hypernasality, and air escape with speaking. Primary closure in the region of tongue to the cheek with resultant mobility problems as well.

Neurological dysfunction

Neurological dysfunction following treatment of squamous cell carcinoma of oral cavity commonly involves sacrifice of the lower division of trigeminal nerve as well as facial nerve weakness.

Loss of cranial nerve V produces sensory deficit that may further compound speech and swallowing problem . limited ability to create an oral seal is seen with denervation of muscles of mastication .with loss of lower branches of facial nerve orbicularis and buccinator function is impaired. Cranial nerve IX provides sensation to the tonsillar region, palate, posterior third of tongue and the pharynx as well as motor function to part of soft palate and pharyngeal constrictor muscles. With loss of this nerve’s function, the gag reflex is impaired and the uvula is found to deviate. Dysfunctioning of vagus nerve results in the most severe swallowing disabilities and predisposes to aspiration. Cranial nerve XII gives motor innervation to the tongue. Loss of its function worsens articulation and the swallowing problems seen with glossectomy and floor of mouth resection.

Wound breakdown and fistula formation

Intraoral wound breakdown is often associated with radiation therapy and can result in contamination of deep spacer within the neck by saliva and other oral contents. Use of regional musculocutaneous and axial flaps that have cutaneous portions with inconsistent vascularity. Similarly predisposes to intraoral wound breakdown if the blood supply is compromised by torsion of the pedicle. Marginal necrosis of distal portion of the flap may also progress to frank wound breakdown.

Complications of reconstruction plates

Early complication of reconstruction plates include wound dehiscence and exposure. Late complication were pain, plate exposure, chronic infection, loose screws and plate fracture. Complications were observed from between 3 and 24 months postoperatively and in all patients who received radiotherapy.

Reconstruction of patients undergoing hemi maxillectomy with obturators will be difficult if the surgeon doesn’t decide the teeth that are ideal to use as abutments preoperatively.

Complications associated with surgical treatment of neck

The radical neck dissection as first described by Crile in 1906 was considered the only analogically safe operation for the treatment of lymph node metastasis to the neck for various head and neck primary malignancies.

Shoulder dysfunction and pain

Shoulder dysfunction and pain were long associated with the radical neck dissection. In 1961, Nahacin and colleagues described “shoulder syndrome” which consists of pain in the shoulder, limited abduction of the shoulder , anatomic deformities such as scapular flattening , shoulder droop and protraction. With the sacrifice of spinal accessory nerve and denervation of trapezius muscle, the scapula can no longer be stabilized. It tends to flare out at vertebral border, slip forward and downward, and thereby limit the ability of the shoulder to move in full active range of motion. Shoulder dysfunction following neck dissection is seen to be a complex and multifactorial problem. With the preservation of 11 th cranial nerve , even in the case of excessive dissection , tissue appear to be the most important factor in improvement of shoulder disability.

Cranial nerve injury

Potential injury to the hypoglossal nerve during neck dissection that evolves the submandibular triangle cases. Functional impairment of the intrinsic tongue musculature as well as hyoglossus, styloglossus, and genioglossus muscles. Palsy of cranial nerve XII, results in paralysis of the ipsilateral tongue as well as interfere with the elevation and depression of larynx which are so important to the swallowing mechanism.

Preservation of marginal mandibular branch of facial nerve helps to spare patients from significant facial deformities post operatively.

Complications associated with radiation treatment for head and neck cancer

Ionizing radiation has been successfully for the treatment of head and neck cancer for greater than 60 years. Although associated complications and efforts on normal tissue(bone, skin and salivary glands) are often described, well documented, incidence rates are difficult to ascertain. Radiation associated complications describe both acute problems often noted within weeks of completion of therapy, and later effects, which involve damage to more slow growing tissue and are noted 6-12months after treatment. The so called stochastic effects of radiation, such as the induction of secondary neoplasia, have also been described.

The commonest described problems of xerostomia, loss of taste, and mucositis are unavoidable and with proper patient education, are managed with supportive measures. some of the more serious complications, such as soft tissue ulcerations, the development of orocutaneous fistulas and ORN may be the result of overly aggressive treatment or faulty technique.

On the skin and mucous membrane

a. mucositis

- prominent in 1st to 2nd week, peak in 4th to 5th week
- cleans shortly after or at completion of therapy
- occurs when rate of epithelial growth and repair is exceeded by effects of radiation, resulting in an epithelial thinning, erosion and ulceration.
- First sign-white appearance of mucosa due to hyper keratinization and intraepithelial edema or red appearance due to hyperaemia.
- Pseudomembrane formation most likely represents ulceration with fibrinous exudates with oral debris and microbial components.
- Non keratinized mucosa is involved first
- Late changes in mucosa-endarteritis and vascular changes with hypovascularity and hyalinization of collagen
- Oral defences are compromised-
Decreased mucosal turnover, increased permeability and loss of mucosal barrier, changes in saliva secretion, decreased levels of antimicrobial factors in saliva, loss of protective mucous and diluting effects.
- Impairment of mobility of oral structures leads to decreased cleansing of local irritants and food products.

b. Xerostomia

- Results from the direct effect on major salivary glands
- Parotid and submandibular glands produce 55-80% of total salivary flow
- Salivary glands are affected when upper limit of field is at chin to mastoid
- Doses greater than a total dose of 3000gray poses a risk if all the major glands are in the field of radiation.
- Irreversible effects occurs with a total dose of 6000gray for 5 weeks
- Decrease in the rate of salivary flow occurs in the 1st week of treatment due to atrophy and necrosis of acinar cells, changes in the vascular connective tissues and altered neurologic function
- Serous acini are affected earlier. This resulted in thick and viscous secretions.
- Changes in the comparisons of saliva results due to decrease in secretory IgA and buffering capacity and acidity. This affects microbial flora and remineralising property of teeth

On bone

a. Osteoradionecrosis

It is an indefinite risk which may even occur several years after cessation of radiotherapy and generally depends on the radiation dose. ORN occurs with greatest frequency in mandible than in maxilla.(24:1) due to its more compact bone composition and less adoptive vascular circulation. Significant causes for the development of ORN are periodontal and dental pathology as well as tooth extractions shortly before, during, or shortly after radiation. Edentulous patients have a lesser risk to develop ORN than dentate patients. ORN is generally accompanied by an intense pain, additional findings are sequestration and even pathologic fracture of affected bone.ORN is actually not a primary infection of bone consequence to diminished vascular supply induced by radiaton. One of the main attraction seen to be obliteration of inferior dental artery which brings about hypovascularity & hypoxia to affected area with resultant ischemic necrosis of bone initially ORN.

b. Candidiasis

- Oral candidial infection has to been frequently repeated in patients undergoing radiotherapy and in same cases, it extends to the respiratory systems including the lungs.
- Fungal infection caused by candida
- Basically 3 types -Pseudomembraneous candidiasis , Chronic Hypoplastic Candidiasiss , Atrophic Candidiasis
- Symptoms vary from painless to burning sensation to sever tenderness .Pseudo membranous infection shows as fine whitish deposits on the oral mucosa, which leaves bleeding surface on wiping.

Management

The majority of cases of post-treatment complications in patients undergoing radiotherapy cannot be prevented. However, with proper pre-treatment management the length and severity of those complications can be reduced. The best approach for the management of these patients is prevention. A careful clinical and radiographic exam of the oral cavity pre-treatment will reveal any alteration in soft tissues, periodontal apparatus, teeth and bone. The mouth must be brought to a healthy status before radiation or chemotherapy whenever possible. There is no one pre-radiation or pre-chemotherapy oro-dental treatment planning for all the patients. Each patient is a unique case that must be dealt with according to the individual needs. The following are basic recommended procedures:

1. Careful evaluation of the periodontium and teeth with special attention to inflammatory foci and periapical lesions. The periodontal status should be maintained at top level of hygiene as well as the rest of the oral cavity. The danger of ORN increases when the healing potential of the oral tissues is threatened by lowered hygiene and microbial infection especially of periodontal origin.

2. During chemotherapy and radiation therapy periodontal management should be restricted to emergency treatment only. Extensive periodontal surgery is not recommended because of possible prolonged healing of tissues. Its is therefore essential to complete all needed periodontal treatment prior to radiation and chemotherapy.

3. Optimal oral infection control by means of chlorhexidine rinses or other antimicrobial mouth rinses.

4. Elimination of any source of traumatic irritation to soft tissues i.e. sharp teeth edges, restorations overhang, ill fitting dentures.

5. Ablation of any hypertrophic (redundant) soft tissues i.e fibroma, polyps, denture injury tumors, granulomas, etc.

6. It is always advisable to wait a minimun of 1 week to 10 days after extraction before starting radiation therapy. Whenever possible longer waiting periods (2 or 3 weeks) are preferable. All questionable teeth should be extracted prior to radiation.

7. If extractions must be done after radiation therapy the use of hyperbaric oxygen pre-extraction should be considered. When extractions are done a carefull remodeling of the alveolar bone should be effected in order to avoid protruding edges which could be starting points of osteonecrosis.

8. Topical fluoride applications with 1% Na fluoride gel for 5 minutes a day or fluoride rinses are recommended. Custom build trays for fluoride application are also recommended. These applications will fortify the enamel in order to prevent rampant caries as a consequence to xerostomia induced by salivary glands impariment after radiation.

9. Every effort should be undertaken in order to preserve teeth which will be important in supporting restorative appliances after the cancer treatment is completed.

10. A controlled diet in order to avoid foods that will facilitate plaque accumulation and caries initiation is also an important recommendation.

11. The patient should be carefully instructed in the daily maintenance of oral hygiene by means of tooth brushing, preferably with a fluoride tooth paste, flossing and control of dental plaque.

12. It is highly suggested that the patient be given written instructions to avoid mistakes and to prevent accidental damage to the soft oral tissues by brushing or flossing.

13. Patients must not use alcohol or tobacco products as these increase the irritation of oral mucosas as well as increasing the risk of new tumor development.

If the treatment is going to be radiation therapy then the following should also be observed:

protect all anatomical structures that do not require radiation with appropriate metal shields and precisely focused radiation.

a. try to protect one or more major salivary glands in order to avoid extreme xerostomia.

b. during radiation therapy metal restorations, such as gold crowns and dental implants, can cause forward and back scatter radiation with resultant mucositis. Special buccolingual guards can be constructed to prevent this from occurring (25).

c. the total radiation dose should be limited to a maximum of 70 Gy.

d. limit the fractioned doses to a maximum of 2 Gy.

Oral Regimen for Patients Receiving Radiation Therapy

The following are general guidelines to be individualized by your doctor. Follow your doctor's advice or discuss any questions with your doctor.

Rinses

1. Rinse with a warm, dilute solution of sodium bicarbonate (baking soda) or salt & bicarbonate (also commercially available as Sage Salt & Soda Rinse) every two hours to bathe the tissues and control oral acidity. Two teaspoons of bicarbonate (or one teaspoon of table salt plus one teaspoon of bicarbonate) per quart solution is recommended.

2. If you are experiencing pain, rinse with one teaspoonful of elixir of Benadryl before each meal. Be careful when eating while your mouth is numb to avoid choking.

3. If your mouth is dry, sip cool water frequently (every ten minutes) all day long. Allowing ice chips to melt in the mouth is comforting. Artificial salivas, eg, Sage Moist Plus spray, Moi-Stir, Salivart, Xero-Lube, Orex, can be used as frequently as needed to make the mouth moist and slick. A mouth moisturizing gel, ie Sage Mouth Moisturizer or OralBalance gel may be helpful when applied to the gums. Keep the lips lubricated with petrolatum or a lanolin- containing lip preparation. Commercial mouthrinses with alcohol bases, coffee, tea and colas with caffeine should be avoided as they tend to dry the mouth.

4. If oral yeast infection develops, antifungal medications can be prescribed.

a. Nystatin pastilles*; let one dissolve in the mouth five times a day, or

b. Let a 10 mg clotrimazole (Mycelex)* troche dissolve in the mouth five times a day,

c. Swish with Nystatin oral suspension for two minutes timed by a clock. Either spit out or swallow, as directed by your dentist or physician.

Care of Teeth and Gums

1. Floss your teeth after each meal. Be careful not to cut the gums.

2. Brush your teeth after each meal. Use an ultrasoft, even-bristle brush and a bland toothpaste preferably containing fluoride, eg, Aim, Crest, Colgate. Brushing with a sodium bicarbonate - water paste is also helpful, Arm & Hammer Dental Care toothpaste and tooth powder and Sage Mouthpaste dentifrice are bicarbonate based. If a toothbrush is too irritating, cotton-tip swabs (Q-tips) or foam sticks (Sage Ora-Swab or Toothette) can provide some mechanical cleaning.

3. A pulsating water device, eg, Water-Pik, Hydrofloss or Viadent irrigators, will remove loose debris. Use warm water with 1/2 teaspoonful each of salt and baking soda and low pressure to prevent damage to tissue.

4. Have custom, flexible vinyl trays made by your dentist to self- apply fluoride gel to the teeth for five minutes once a day after brushing.

5. Rinse with an antiplaque solution (Peridex) two or three times a day when you cannot follow other oral hygiene procedures, if prescribed by yout dentist.

6. Follow any alternative oral hygiene instructions prescribed by your dentist,

Nutrition

Adequate nutrition and fluid intake are very important for oral and general health. Use diet supplements eg, Carnation Instant Breakfast, Meritene, Ensure. If your mouth is sore, a blender may be used to soften food.

Maintenance

Have your oral health status reevaluated at regularly scheduled intervals by your dentist.

Supportive

A humidifier in your sleeping area will alleviate or reduce nighttime oral dryness. Be sure to properly clean unit to prevent bacterial and fungal buildup.

The above regimen is also applicable to patients with oral problems associated with HIV and AIDS.

As stated earlier the most important therapeutic measures for patients undergoing radio- or chemotherapy is prevention. Their oral cavity should be conditioned and free of any inflammatory source as much as possible. Patients can be placed on antifungal and antimicrobial medications (10) a frequently used protocol is:

Abbildung in dieser Leseprobe nicht enthalten

Ask the patient to mix 1 part of hydrogen peroxide in 6 parts of warm water and add a dash of salt. Instruct to intraorally swish this mixture for 2 to 4 minutes several times a day. This is a good alternative to chlorhexidine.

For active mucositis:

1. a bland and liquid diet avoiding alcohol, caffeine or any other irritant such as tobacco products. Food should be lukewarm.

2. rinse the mouth frequently with a mixture of 1/2 tsp each of baking soda and salt dissolved in a large glass of warm water

3. to reduce inflammation prescribe:

Abbildung in dieser Leseprobe nicht enthalten

First day 2 tablets then, 1 tablet per day.

Xerostomia can be ameliorated by any of the commercially available saliva substitutes wich are obtained OTC, such as: Moi-Stir, Orex, Sage Moist Plus, Salivart, Xero-Lube and some others. Patients should be advised to keep their sleeping area highly humid. Prevention of rampant caries which occur as a consequence to xerostomia is achieved by prescribing:

Abbildung in dieser Leseprobe nicht enthalten

Recommend the use of toothpaste containing fluoride. There are a variety of stannous fluoride gels available in the market such as:Flo Gel, Nova Gel, Ommni Gel, Thera-Flur among others.

The best treatment of ORN is prevention, as previously mentioned, but if in spite of it osteonecrosis develops then the following treatments, alone or in combination, can be utilized:

1. hyperbaric oxygen (HBO) treatment consists of 90 to 120 minutes sessions (each session is called a dive) in a single or multiplace chamber at 2 to 3 atmospheres absolute pressure, breathing 100% oxygen by mask. The number of dives varies with the extent of ORN. The aim of HBO treatment is revascularization of bone and soft tissues. Oxygen in hypoxic tissues induce fibroblast growth and new capillary formation.
2. long term intravenous antibiotics, generally in daily doses of 1 million units of penicillin G and in severe cases followed by feneticillin 625 mg orally 4 times a day for 1 week. This treatment also varies with the degree and extent of ORN.
3. surgical removal of the necrotic bone.
4. if facial deformity ensues as a consequence to surgery then reconstruction can be obtain with autologous bone grafts or microvascular osseous grafts.
5. intraoral or facial prosthetic reconstruction is also a means of treatment (4).

Loss of taste

- May occur as a 10 effect of radiation or 20 to xerostomia
- Doses less than 2000 rad decreases taste activity
- Complete subjective loss is seen at 3000 rad which recovers 60-120 days after the completion of the treatment.

On teeth

Radiation caries

- Patient with increased number of >105 streptococcus mutans& 104 lactobacillus are considered to be at high risk or causes development.

- Usually caries is associated with xerostomia. These radiations cause affects the gingival third & cervical cusp tips of teeth.

Etiology

- Lack of production of saliva results in lossof remineralisation potential.
- Loss of buffering capacity of saliva.
- Increased acidity of saliva
- Change in bacterial flora of saliva.

Management

- Oral hygiene maintenance
- Manage xerostomia
- Use of flourides to harden tooth structure
- Topical flourides & chlorhexidine rinses to reduced levels of streptococcus mutans.

Dento facial Anomalies

- Growth and development is affected mainly in children

- There is agenesis of teeth, roots ,abnormal root formsor calcification.
- Growth of facial skeleton is also affected resulting in micrognathia or retrognathia. Maxillary growth may also be altered. The patient may present with asymmetric facial growth.
- Trismus may result due to fibrosis of muscles
- Due to Mucositis, Necrosis of soft tissue, myofacial & musculoskeletal syndrome.
- Exacerbation of dental or periodontal disease.

Management of Pain

Dental and periodontal disease pain – analgesics and antibiotics are definitive treatment.

Mucositis :

- Bacterial ,fungal & viral infection –antimicrobial agents
- Mucosal infection – topical antifungal & antiseptics
- Neurologic pain – antidepressants and anti convulsants.

Mild to moderate pain -non-narcotic analgesic (acetaminophen, NSAIDS)

Severe pain – Non –Narcotic and potent narcotic (codeine adjuvant medication)

Endocrine abnormalities

The development of endocrine abnormalities is a complication of radiation treatment has been most extensively received in the neurological literature in cases of hypothalamic and pituitary exposure.samaan and colleagues received 66 patients received with radiation therapy for carcinoma of nasopharynx, paranasal sinuses, 0 of whom received neck irradiation, with a medium dose to the thyroid of 5000rad. Patients were followed for upto 5 years. 48 of the 10th patients demonstrated evidence of 0 hypothyroidsm on biochemical testing that consisted of serum thyroid-stimulating hormone, total serum t4, serum t3 and resin uptake measurements.

Favus and co-worker reported on the incidence of thyroid carcinoma as a late consequence of head and neck irradiation. Parathyroid abnormalities have similarly been reported in patients receiving radiation to the neck. This area needs further investigation with long periods of observation.

Visual impairment

Radiation to visual apparatus may accompany the treatment of tumors of maxilla, maxillary sinus, orbit and ethmoid and sphenoid sinuses. Reported complications include the development of radiation keratitis, cataract formation, optic neuritis with progressive visual loss. The incidence of radiation damage to optic nerve and chiasma is related to both the total dose and fraction sites. Because fraction sites of 50 rads per fraction may lead to blindness, whenever possible, fraction size should be kept below this level.

Radiation neuritis

Radiation neuritis of other cranial nerve is a reported complication of treatment of head and neck tumors. The occurence is uncommon and the incidence can be markedly reduced, if the total dose to neural structure is kept below 7000 rads in 7 weeks.

Complications associated with chemotherapy for head and neck cancer

Chemotherapy remains an important part of adjuvant therapy for advanced cancers of the head and neck as well as the treatment of recurrent tumors. The value of treating head and neck cancer patients with chemotherapy before surgery or radiation therapy remains controversial. The national cancer institute contracts programme showed no benefit from the addition of chemotherapy whereas several more aggressive pilot studies have demonstrated a better two year survival. The chemotherapeutic agents most commonly used for the treatment of head and neck epidermoid carcinoma are cisplatin, bleomycin, 5-fluorouracil, methotrexate and vincristine.

The toxicity associated with each of the preceeding agents well documented. Nausea, vomiting, diarrhoea, stomatitis and shortness of breath are commonly reported. If associated gastrointestinal symptoms are severe, intravenous nutritional support may be required. Renal toxicity is usually characterized by a transient elevation in blood urea nitrogen and creatinine, which almost reserves itself and rarely results in the need for electrolyte repletion. Haematologic toxicity is gently reported as mild for most regimes received. Leucopenia is more severe in multi agent protocol. Thrombocytopenia is very mild throughout treatment.

Stomatitis of a serious nature is reported in 25% of patients and need to be managed with appropriate supportive care. Ototoxicity is usually minimal. High frequency hearing loss is most commonly reported but is less than 10dB. Hypertension during infusion has been noted with the use of cisplatin. Persistent dyspnoea without obvious cause have been reported.

References

1. Adamietz IA et al. Prophylaxis with povidone-iodine against induction of oral mucositis by radiochemotherapy. Supportive Care in Cancer 1998;6373-7.

2. Baliga AM et al. Oral mucosal lesions in patients with acute leukemias and related disorders due to cytotoxic therapy. J Indian Soc Pedodont Prevent Dent 1995;13:25-9.

3. Barasch A et al. Helium-neon laser effects on conditioning- induced oral mucositis in bone marrow transplantation patients. Cancer 1995;76:2550-6.

4. Bunetel L; Bonnaure-Mallet M. Oral pathoses caused by Candida albicans during chemotherapy: update on development mechanisms. Oral Surg Oral Med Oral Path Oral Radiol Endodon 1996;82:161-5.

5. Carl W. Oral complications of local and systemic cancer treatment. Current Opinion in Oncol 1995;7:320-4.

6. Cowen D et al. Low energy Helium-Neon laser in the prevention of oral mucositis in undergoing bone marrow transplant: results of a double blind randomized trial. Internat J Rad Oncol Biol Physics 1997;38:697-703.

7. Feber T. Management of mucositis in oral irradiation. Clin Oncol (Royal College of Radiologists) 1996;8:106-11.

8. Foote RL et al. Randomized trial of a chlorhexidine mouthwash for alleviation of radiation-induced mucositis. J Clin Oncol 1994;12:2630-3.

9. Kennedy L; Diamond J. Assessment and management of chemotherapy-induced mucositis in children. J Ped Oncol Nursing 1997;14:164-74

10.
Maciejewski B et al. Randomized clinical trial on accelerated 7 days per week fractionation in radiotherapy for head and neck cancer. Preliminary report on acute toxicity. Radiotherapy Oncol, 1996;40:137-45.

11. Mahood DJ et al. Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol 1991;9:449-52.

12. Marks JE. Mucosal protectants and their application for head and neck chemoirradiation. Current Opinion in Oncol 1997; 9:267-73.

13. Parulekar W et al. Scoring oral mucositis. Oral Oncology 1998;34:63-71.

14. Ramirez-Amador V et al. Chemotherapy-associated oral mucosal lesions in patients with leukaemia or lymphoma. European J Cancer. Part B, Oral Oncol 1996;32B:322-7.

15. Rees TD et al. Periodontal considerations in the management of the cancer patient. J Periodontol 1997;68:791-801.

16. Rovirosa A et al. Granulocyte macrophage-colony-stimulating factor mouthwashes heal oral ulcers during head and neck radiotherapy. Internat J Radiation Oncol, Biol, Physics 1998;41:747-54.

17. Ruescher TJ et al. The impact of mucositis on alpha-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematologic malignancies. Cancer 1998;82:2275-81.

18. Scully C; Epstein JB. Oral health care for the cancer patient. European J Cancer. Part B, Oral Oncol, 1996;32B:281-92.

19. Silverman S. Oral Cancer 4th Edit. Amer. Cancer Soc. B.C.Decker Inc. 1998, Chapters 6 and 7.

20. The American Academy of Oral Medicine. Clinician's Guide to Treatment of Common Oral Conditions, 1993.

21. Toth BB et al. Oral complications associated with cancer therapy. J Clin Periodontol 1990;17:508-15.

9. Management of terminally ill patients

Management of terminally ill patients is now known as palliative care. Palliative care is an approach that improves quality of life of patients and their families facing the problems associated with life threatening disease, through the prevention and relief of suffering, by means of early identification, impeaceable assessment of treatment of pain and other problems – physical, psychological and spiritual(1).

The goals of palliative care can be summarized as;

(1) Provide relief from pain and other distressing symptoms.
(2) Affirm life and regard dying as a normal process.
(3) Intend neither to hasten nor to postpone death.
(4) Integrate the spiritual psychosocial aspects of patient care.
(5) Offers support system to the family to cope during the patients illness and patients bereavement.
(6) Offers support system to help patient leave as actively as possible until death.
(7) Use a team approach.
(8) While enhancing the quality of life, it may also possibly influence the cause of the disease.
(9) Palliative care can be given early along with radiotherapy or chemotherapy, that are intended to prolong life.
(10) Include investigations needed to better understanding and management of distressing clinical complications.

Oral cancer is a leading cause of death in our country. So palliative care is an area of high priority in cancer care.Early symptoms can be treated by simple modalities by a dental practitioner. The radiation oncology specialists may not have enough time once radiation is completed to manage the complications of radiation. Palliative care not only considers the management of distressing symptoms but also prepares the patient to face death with courage. It also includes support of concerned family members.

Most important symptoms of patients with advanced head and neck cancers are;

(1) Pain
(2) Dryness of mouth or xerostomia
(3) Foul smelling necrotic ulceration and mucositis.
(4) Bleeding
(5) Dysphagia
(6) Radiation caries
(7) Osteoradionecrosis
(8) Secondary fungal/bacterial infections.(2)

(1) PAIN:

It is an unpleasant, sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Cause of pain in a cancer patient may be invading cancer (eg: tissue invasion), treatment (eg: mucositis), debility(eg: bed sores) or concurrent disorders(eg: spondylosis, osteoarthritis).

Pain may be acute or chronic pain. Acute pain is usually well defined following acute injuries or illness lasting days or weeks, often accompanied by sympathetic over activity and some anxiety. Chronic pain is often ill defined lasting for months or years, often accompanied by depression but no sympathetic overactivity. Chronic pain worsens in intensity and extends when left untreated.

Pain may also be classified into nociceptive pain and neuropathic pain. Nociceptive pain is due to tissue injury or distortion. It may be somatic (damage to skin and deep tissues) or visceral(damage to abdominal and thoracic viscera). Neuropathic pain is the pain that arises from injury, disease or dysfunction in peripheral or central nervous system. Incidence of neuropathic pain in cancer is about 30%-50%. Neuropathic pain can be recognized by its nature( burning, aching, shooting, lancinating), distribution(neural or dermatomal) and less responsive to opioids. Abnormal sensations like allodynia may also be present. Many pains are combined i.e nociceptive+ neuropathic.

Pain assessment should be thorough and rapid. Avoid unnecessary delay in treating pain, especially if it is severe. Treatment should aim at relief and prevention of pain. Drugs selected should be appropriate for type of pain and appropriate for severity of pain. Follow WHO analgesic ladder.

ANALGESIC LADDER

Abbildung in dieser Leseprobe nicht enthalten

They are narcotic drugs used to treat severe excruciating pain. In someone presenting with excruciating pain, it may be necessary to go to step 3 right way, if necessary I/v route. Most commonly used drug is Morphine. Various preparations of Oral morphine available at palliative care clinic include Morphine Sulphate tablets (10 mg, 20 mg, 50 mg); Cap Morphine Sulphate 5 mg, 10 mg, 20 mg; Morphine Solution CCS 1ml = 5 mg. Double dose at bedtime is used to manage pain at night. If pain relief is not satisfactory, increase by approximately 50% of previous dose. There is no upper limit for morphine when given for pain.

Opioid side effects include, constipation, drymouth, nausea, vomiting, drowsiness, tiredness, anorexia, urinary hesitancy and itching.

Adjuvant Analgesics

They are drugs which are not per se analgesics but acts as analgesics in certain situations. They are:

1) Sedatives ( Barbiturates, Benzodiazepenes like diazepam)
2) Antidepressants ( Amitriptilline)
3) Anticonvulsants( Carbamazepine, gabapentine)
4) Tranquilizers
5) Corticosteroids
6) Mood elevators

These are useful in the treatment of neuropathic pain.

Three most important points to be remembered are:

1) Give correct dose of drug by mouth whenever possible
2) Give drug by clock depending upon duration of action of each individual drug till death.
3) Tailor the treatment to the individual needs of the patient.(4)

2) DRYNESS OF MOUTH /XEROSTOMIA

Most important complication of cancer treatment following radiation therapy due do destruction of salivary glands is xerostomia. Patient experiences pain and difficulty while swallowing. Pilocarpine is the best studied sialogouge. Doses up to 15 mg/day, causes increased secretion of saliva. Bethanecol ( 75-200 mg/day in divided doses) and Bromhexine also causes increased saliva secretion. These are the various synthetic saliva available. But oral cancer is a poor man’s disease. So the synthetic saliva used in palliative care is not affordable to most of the patients. An equivalent of synthetic saliva can be made using various components at home.

Composition of home made salivary substitution:

Sodium chloride - 2 gram

Sodium bicarbonate - 2gram

Lime juice – 10 drops

Aristozyme – 10 drops

Top up to 1 liter of water(5)

Home made saliva can be used to swish the mouth to help mastication and deglutition and to moisten the mouth. There should be clinical trials to compare costly agents with home made substitutes.

3) FOUL SMELLING NECROTIC ULCERS AND MUCOSITIS

The foul smell is due to infection with gram negative bacteria. Metronidazole gel can be used to dress fungating and foul smelling ulcers. Mashed papaya is an excellent dressing for necrotic ulcers.

MUCOSITIS

Ulcerative oral mucositis is a painful and debilitating condition that is a dose and rate limiting toxicity and cancer therapy. The potential sequlae of mucositis consist of severe pain, increased risk for local and systemic infections, compromised oral and pharyngeal functions and oral bleeding that affect quality of life. It is most common cause of pain during cancer treatment. Pain due to oropharyngeal mucositis frequently requires the use of opioid analgesics.

Management of mucositis includes:

a) Diluting agents

Saline, bicarbonate rinses, frequent water rinses, dilute hydrogen peroxide rinses.

b) Coating agents

Kaolin pectin, aluminium chloride, aluminium hydroxide, magnesium hyrdroxide,sucralfate.

c) Lip lubricants

Water based lubricants, lanolin

d) Topical anesthetics

Xylocaine HCL, benzocaine HCL, dyclonine HCL

e) Analgesic agents

Benzydamine HCL.

4) BLEEDING

Bleeding in oral cancer is due to invasion of cancer cells into blood vessels which may lead to profuse bleeding to death. So patient may be informed about the risk of bleeding. As a first aid measure it can be stopped by pressure application

Other methods include:

Cauterisation,sutures and ligation,local agents like astringents and styptics, bonewax, thrombin ,gelfoam,oxycel ,surgicel,fibrin glue and adrenaline. In extreme cases ligation of external carotid artery may have to be performed.

5) DYSPHAGIA

Occurs due to mucositis of oral mucosa, obstruction due to large sized tumour, due to enlarged lymph nodes pressing on the oesophagus.

Treatment of dysphagia includes management of pain and mucositis along with surgical removal of large sized tumour and lymphnodes if indicated. Patients with difficulty to intake liquid food may be fed through a nasogastric tube.

6) RADIATION CARIES

It is a rampant form of dental decay that occurs as a complication of radiation therapy. The best method for reducing radiation caries is daily application of 5 minutes of viscous topical 1% neutral sodium fluoride gel. Use of topical fluoride causes a delay in irradiation induced elevation of Streptococcus mutans. Avoidance of dietary sucrose also reduces S. mutans and Lactobacillus.The best result is achieved from a combination of restorative dental procedures,excellent oral hygiene and topical application of sodium fluoride. Patient co-operation in maintaining oral hygiene is extremely important. Teeth with gross caries or periodontal involvement are often extracted before irradiation.

7) OSTEORADIONECROSIS

It is the most serious complication which occur in bone after irradiation. Osteoradionecrosis is an exposure of nonviable, nonhealing, nonseptic lesion in the irradiated bone, which fails to heal without intervention.

Conservative treatment includessystemic antibiotics selective rinsing with topical antiseptics , selective removal of small sequestra , curetting and local debridement,burring it out until normal bleeding bone appears. One of the most recent adjuvant therapy for the treatment of osteoradionerosis is HyperbaricOxygen therapy (HBO).

8) SECONDARY FUNGAL/BACTERIAL INFECTIONS.

Another complication of oral cancer in a terminally ill patient is secondary viral,fungal and bacterial infection. Candidiasis is the most important fungal infection. Candidiasis treatment includes use of flucanazole,cotrimazole. HSV is the most important viral infection. Topical antiviral drugs can be used.Gram negative bacterial infection is another complication in a terminally ill patient.Oral lozenges containing polymixin,tobramycin and amphotericin B and other topical antiseptics can be used.

Myiasis is another infestation in terminally ill stage.Myiasis involves invasion of vital tissue of humans by fly larvae. The eggs deposited by the flies hatch into larvae, which burrows deep into tissue and destroy it. There is a higher risk of infestation in individuals with poor hygienic conditions, suppurative oral lesions, senility, mouth breathing during sleep, alcoholism, paralysis. Treatment of myiasis involves local and systemic measures. Local measures include application of larvicidal agents like turpentine, ether, chloroform, kerosene, ethyl chloride, butazolidine, creosote etc . Systemic measures include general care of patient and the use of broad spectrum antibiotics.Infected patients should be exposed to relevant intervention as early as possible to prevent complications.

All the above symptoms can be managed in a local dental clinic. Palliative care services require skills in the following areas.

1) Communication
2) Decision making
3) Management of complication of treatment and disease
4) Management of pain and other distressing symptoms
5) Psychosocial care for patient and family
6) Spiritual understanding and approaches
7) Care of dying
8) Bereavement care.

Dentist plays a major role in palliative care and treatment. Traditional oral hygiene care may not be appropriate for acutely sick, non responsive or terminally ill patients.In conclusion it can be stated that palliative care is a key component of overall cancer control plan that responds to needs of an advanced cancer patients and their families. Palliative care should be linked to cancer prevention, early detection and prompt treatment.

1. The role of dental surgeons in palliative care; association of stomatologists and maxillofacial imageologists of Kerala.

2. Ant D. An investigation into relationship between salivary gland hypofunction and oral health problems in patients with advanced cancer. Dissertation, Kings College, London:2004.

3. Babu Mathew, R. Sankaranarayanan HF Stitch MK Nair; Chemoprevention of precancerous oral lesions in tobacco usere. Chemoprevention of cancer. Eds S Bhide Maru. R. published fromTata Memorial Hospital, Bombay 1994, p- 91-97.

4. Stjernsward J, Clark D. Palliative medicine: A global perspective. In: Doyle D, Hanks G, Cherney N, Caiman K(editors). Oxford textbook of palliative medicine, 3rd edition.oxford medical publication: Oxford; 2003. P. 1199-224.

5. Rajagopal MR, Venkateswaran C. Palliative care in india: success and limitations. J Pain Palliat Care Pharmacother 2003;17:121-8.[ PUBMED].

10. Research scenario of oral cancer

Introduction:

With 300,000new cases diagnosed worldwide, Oral Cancer continues to be a major global public threat. In Indian sub-continent, oral cancer accounts for 30 – 40 % of all cancer types. Oral and pharyngeal carcinomas comprise up to half of all malignancies in India and other Asian countries. Based on the epithelial origin, majority are classified as oral squamous cell carcinomas (OSCC). Although OSCC which represents more than 90% of all oral cancers , is the most common type of oral cancer, there are dozens of other pathologic diagnoses. . The prognosis for patients with OSCC remains poor, with a 5 year survival rate that has not changed significantly for several decades, despite refinement of surgical and adjuvant treatment modalities. This is mainly attributed to delay in cancer diagnosis and development of second primary cancers. Early detection of oral cancer is still considered as the most effective way to improve survival .In this regard, early detection of oral premalignant lesions and conditions is quite important as it may help in prevention of oral cancer.

Oral carcinogenesis and field cancerization theory

Oral carcinogenesis is considered as a multistep and multifocal process involving field carcinogenesis and intraepithelial clonal spread. According to the field cancerization theory an area of mucosa can sustain an initial genetic injury and proliferates in a premalignant state. Additional genetic changes will result in progression to overt carcinoma in individual sub sites.

The observation that oral cancer develops in multifocal areas of precancerous changes and the finding that histologically abnormal tissue surrounds the tumor has led to the field cancerization theory of oral carcinogenesis. Braakhuis etal (2005) had proposed the progression model for OSCC focusing on the genetic characterization of field cancerization. According to this model, initially a stem cell located in the basal cell layer of the mucosa acquires a genetic alteration which subsequently results in the formation of a patch, defined as a clonal unit consisting of the stem cell with its daughter cells that all share the part alterations.

This is accompanied by a series of histopathological stages from hyperplasia to dysplasia of varying degrees and to carcinoma in situ prior to the development of invasive squamous cell carcinoma (Hunter etal , 2005). The next crucial step in this process is the change of a patch into an expanding field as a result of additional genetic alterations. This mucosal field pushes the normal epithelium aside and can expand to a size of several centimeters. Even though fields are often macroscopically invisible, this may appear as oral patches. Finally clonal selection leads to the development of carcinoma within this field of preneoplastic cells.

Risk factors

Tobacco chewing/smoking and alcohol consumption are considered as major aetiologic factors in the development of oral cancer (Choi and Kahayo 1991; Notani 2000). Betel quid chewing (BQC) is a widespread habit in India and10-20%of world’s population is considered to chew betel quid or areca nut in some form (Gupta and Warnakulasuriya, 2002 ). As far as Indian scenario is considered, tobacco chewing and smoking habits are responsible for many cancers of the oral cavity and oropharynx . Tobacco usage in the form of reverse smoking ie, smoking with the glowing end inside the mouth, confers a 5.19 times higher risk of oral and precancerous lesions of the palate than did use of chewing tobacco. ( Hebert etal 2002 ). Diets low in vegetables and fruits and high in alcohol increase the risk of oral cancer (Hebert etal 2002).in a rural cohort study from kerala,Jayalekshmi etal(2009) analyzed oral cancer risk among women in relation to tobacco use and socio-economic status .this study showed that oral cancer incidence was strongly related to daily frequency of tobacco chewing(p<0.001)and was increased 9.2 fold among women chewing tobacco 10 times or more a day. The risk increased with the duration of tobacco chewing during the first 20 years of tobacco chewing.

Furthermore, high risk human papillomaviruses have also been implicated as important aetiologic agents, especially in the oral cancers with no tobacco or alcohol associations (Gillison etal, 2000). Human papillomavirus(HPV 16) has been branded as a risk factor in the new proportions of oral cancer victims. Multiple pathways for HPV transmission including perinatal transmission, sexual transmission by oral genital contact, and auto infection from oral genital contact by hand have been proposed.

The current burden of oral cancer in the human population is partly due to the unique susceptibility of human genome to mutational changes and to the numerous environmental factors, including diet and lifestyle which reveal this susceptibility by increasing the opportunities for sustained mutational changes that drives carcinogenesis. Although environmental factors including life style factors play an important role in etiology of oral cancer, genetic variation among individuals is also an important modulating factor in oral cancer susceptibility. It has been documented that some patients appear susceptible because of inherited trait(s) in their ability or inability to metabolize carcinogens or pro-carcinogens, possibly along with an impaired ability to repair DNA damage. Even though all humans are at risk of developing cancer, certain individuals and group of individuals, by virtue of genetic variations they possess, may be more or less susceptible to carcinogenesis.

In India., research on oral cancer has been mainly focused on identification of genetic susceptibility factors and molecular alterations in oral cancer tissues etc, with the hope of identifying biomarkers for early diagnosis and prediction of malignant transformation potential of oral precancerous lesions and conditions and prognosis.

Research on Genetic susceptibility to Oral cancer in India:

It is becoming clear that inter-individual genetic variation play a significant role in the ability of individuals to withstand exposure to exogenous carcinogens or to inhibit initiation, promotion, or proliferation in carcinogenesis. Genetic susceptibility to cancer is determined by two types of genes - high penetrance genes and low penetrance genes.

Familial or inherited high penetrance genes account for only a small proportion (10-15%) of all cases .There have been reports on aggregation of oral cancer in few south Indian families (Ankathil etal 1996) .Fw other reports also have demonstrated that there is an increased risk of oral cancer amongst first degree relatives of patients with head and neck cancer (Cooper etal 1995, Foulkes etal 1996) Despite this, no high penetrance oral cancer susceptibility gene has been identified. In contrast, in the remaining majority of sporadic oral cancers, genetic variations in the form of low to moderate penetrance alleles interacting with environmental factors may predispose individuals to cancer (Chakravarti, 1999). Even though individual low penetrance risk alleles are insufficient to cause cancer, these may influence cancer risk. Single nucleotide polymorphisms (SNPs) which are substitution of a single nucleotide along the DNA are the most common forms of genetic variations. SNPs represent a potentially vast arena for the detection of genetic alterations that seems to relate to medically important differences in disease susceptibility including cancer susceptibility. Functional SNPs may explain a significant portion of complex disease predisposition, treatment response and prognosis, by acting as low penetrance alleles.

It is likely that individuals at differential risk of developing oral cancer are increasingly likely to be identified from germ line DNA, in the form of mutations or SNPs. SNPs in genes involved in DNA repair, cell cycle regulation , apoptosis, signal transduction process etc have been heavily investigated for their contributing role in oral carcinogenesis, because of the mutator phenotype attributable to these genes and their frequent deregulation in carcinogenesis( Loeb 1991).

Molecular epidemiological studies have shown that an individual’s susceptibility to oral cancer is modulated by both genetic and environmental factors. Genetic polymorphisms of phase I and phase II xenobiotic metabolizing enzymes as well as DNA repair genes can modify an individual’s response to carcinogens and hence, the carcinogenic potential of such exposures. There are several but conflicting reports on the association of various SNPs in genes encoding phase I and phase II metabolizing enzymes and DNA repair enzymes with oral cancer predisposition risk .From India, Sreelekha etal ( 2001 ) reported that CYP1A1 (Ileu/Val) genotype was associated with increased risk of oral cancer in kerala population (South India) but Sikdar et al ( 2003 ) could not establish such an association .with oral leukoplakia in Kolkata, Eastern part of the country. In Eastern Indian population, Sikdar et al ( 2006 ) reported that rare C allele at Dra I polymorphic site in CYP2E1 gene enhanced susceptibility to leukoplakia among tobacco users while CYP2E1 PSt1 and Rsa1 polymorphisms were not associated with risk of leukoplakia in this population. In another study by Anantharaman et al ( 2007 ), it was observed that CYP1A1 MspI polymorphism does not independently confer risk to OSCC in Indian population, but confers risk only in association with tobacco exposure.

Several Indian research groups had studied the association of SNPs in genes encoding Phase II metabolizing enzymes. The GSTM1 null genotype was reported to be associated with OSCC susceptibility among tobacco habituals ( Sreelekha et al 2001; Anatharaman et al 2007 ). While researchers from Eastern India reported risk association of GSTM3 ( A/A ) genotype with both oral cancer and oral leukoplakia in smokers, ( Sikdar et al 2004 ), no such risk association was observed for oral cancer and oral leukoplakia from Western India ( Buch et al 2002 ). Furthermore, Majumdar et al ( 2005 ) reported that simultaneous presence of variant genotypes of GSTM3 and XRCC1 genes increased the risk of oral cancer. Few studies ( Sreelekha et al 2001 , Sikdar et al 2004, Sharma et al 2006, Gatoo et al 2008 ) had reported GSTT1 null genotype to be associated with significantly increased risk of oral cancer in Indian tobacco habitual while another study ( Buch et al 2002 ) reported no risk association and yet another study ( Anantharaman 2007 ) reported GSTT1 null genotype to have a protective effect for oral cancer. For GSTP1 polymorphism also, conflicting results had been reported. Sikdar etal ( 2004 ) observed GSTP1 codon 105 polymorphism to have significant risk association with oral cancer whereas Soya et al ( 2007 ) reported no significant risk association.

Researchers had studied the association of SNPs of DNA damage repair genes with oral cancer susceptibility in Indian patients. In a South Indian population, the presence of polymorphic variants of XRCC1 codon 194 and 399 and XPD codon were independently associated with risk of oral cancer (Ramachandran et al 2006). But the study by Majumdar et al ( 2005 ) reported that variant genotypes on three polymorphic sites of XRCC1 ( codon 194, 280, 399 ) and one site on XRCC3 ( codon 240 ) did not modulate risk of oral cancer independently, but simultaneous presence of variant genotypes of GSTM3 and XRCC1 ( codon 290 ) increased the risk of oral cancer .Furthermore, Majumdar et al ( 2007 ) observed that in tobacco users carrying variant genotypes of NAT2 ( N-acetyl transferase-2 ) and XRCC1 and XPD, none of the genotypes could independently modify the risk of OC in Eastern India. But variant genotypes working in two different pathways when present in combination could modulate risk of oral cancer in this Eastern Indian population.

Oral cancer research group from Regional Cancer Centre, Trivandrum, evaluated the association of SNP C81T of H-Ras and the SNPs A870G and C1722G of Cyclin D1 and oral cancer susceptibility risk. H-Ras C81T polymorphic genotypes TC and CC showed higher risk for oral cancer susceptibility in Kerala population and the risk was more pronounced among men on stratified analysis. This study suggested that the variant “C “allele of the H-Ras C81T polymorphism could be considered as a genetic predisposition factor for oral carcinoma. (Sathyan et al 2006). Sailasree et al (2011) investigated the role of MTHFR polymorphism C677T and A1298C on oral cancer susceptibility risk and its potential impact on prognostic outcome. The 677CT + TT genotype showed a significant three fold reduction in oral cancer risk and 1298CC genotype showed decreased cancer risk when compared to AA and AC genotypes. When prognostic significance of MTHFR polymorphism was evaluated, patients with 677CT + TT genotypes showed improved survival than the CC individuals. The 1298 CC and AC +CC showed increased risk for treatment failure and poor survival when compared with the wild type AA genotype. So MTHFR C677T was reported to influence oral cancer susceptibility while A1298C polymorphism was associated with patient prognosis.

From these studies, it can be observed that the effect of polymorphisms in genes encoding phase I and II xenobiotic metabolizing enzymes and DNA repair enzymes show wide variation in risk association in different populations groups. Conflicting results have been observed in different areas for the same gene polymorphism. The contradictory findings among studies could be attributed to the populations’ specific differences in allele frequencies of the SNPs studied, differences in environmental exposures, life style habits, as well as sample sizes and multiple subgroups analysis.

Research on Molecular alterations in Indian Oral Cancer:

Scientific evidences are available which clearly indicates that transition from normal epithelium to premalignancy to oral carcinoma is the result of accumulation of genetic and epigenetic alterations in a multi-step process ( Mithani et al 2006 ). Several single gene studies carried out in 1990’s worldwide, showed that changes in multiple markers were involved in transition steps from normal to precancer to cancer. Genetic alterations usually occur in two classes of genes classified as oncogenes and tumor suppressor genes. Genetic alterations in oncogenes and tumor suppressor genes had been implicated in oral carcinogenesis. All human cells have normal cellular genes known as proto-oncogenes which are involved in normal cellular functions, differentiation and cell regulations. When proto-oncogene is activated by various mechanisms such as point mutation, chromosomal translocation, viral genome integration and amplification, these proto-oncogenes become activated. Activated versions of proto-oncogenes are known as oncogenes which are involved in malignant transformation of a cell. Over expression of oncogenes such as epidermal growth factor receptor ( EGFR ), C-jun, ki-67, Cyclin D and E, p53, Cox-1 and 2 , loss of tumor suppressor genes such as c-erb2, pRB, under expression of p53, p27 etc were reported as molecular markers which correlated with oral epithelial dysplasia and malignant transformation ( reviewed by Pitiyage etal 2009 ).

From India, an earlier study by Chakraborthy et al ( 2003 ) in head and neck squamous cell carcinoma of Indian patients demonstrated high frequency of loss of heterozygosity ( LOH ) in chromosomal region 3p21.31 and this genetic alteration was found to be associated with development of early dysplastic lesions.

Ras genes play a crucial role in normal growth and transformation and a high percentage of Ras mutation had been reported in Indian oral cancer patients ( Saranath et al 1991; Muniraajan et al 1998; Das et al 2000 ) highlighting the important role of Ras pathway in oral carcinogenesis. Sarnath et al (1991) reported H-ras mutations in 39 % of betel quid induced oral cancers in Indian patients. But its validity in the context of oral premalignancy could not be established. So also, over expression of Cyclin D1 , a downstream member of the Ras pathway, has also been reported in a significant percentage of oral cancer patients and Cyclin D1 over expression was shown to be associated with poor prognosis. (Ref)

In Indian oral cancers, a high prevalence of Ras and a lower frequency of P53 mutations were reported, thus indicating demographic variation in mutation spectra from the other parts of world In another study, Sathyan et al (2007) analyzed the co-operative interaction between Ras and B-Raf genes in oral carcinogenesis in Indian patients .This study demonstrated that H-Ras mutation was associated with expression of key cell cycle regulatory proteins such as Cyclin D1, CDK4, RB and p16 in vivo. Furthermore, this study suggested that H-Ras mutated oral carcinoma could be defined as a molecular subtype with favorable outcome and unique biology.

From Regional Cancer Centre, Trivandrum, Sailasree et al (2011) evaluated the genetic and epigenetic status of p16INK4A and p14 ARF genes and assessed the prognostic significance of molecular aberrations in the INK4a locus. In this study, 62 % of oral cancer patients had p16INK4A gene abnormalities, with deletion accounting for 33 % and methylation for 29 %. Furthermore, p14ARF gene alterations, either by deletion (12 %) and /or methylation (18 %) were observed in 30 % of the cases. On evaluating the prognostic correlation of these alterations, p16INK4A deletion was associated with aggressive tumors and initial treatment response. Promoter methylation of p16INK4A was associated with increased disease recurrence and emerged as an independent predictor of worse prognosis. However, p14ARF methylation was associated with lower recurrence in oral cancer patients with a good clinical outcome. From these results, the authors concluded that the molecular profile of INK4A/ARF locus both at DNA and protein level could be used as a prognostic biomarker for assessing the aggressiveness of disease in oral carcinoma patients.

Tumor suppressor genes are major targets in sensing and responding to DNA damage in multi-step process of carcinogenesis. A lot of work has focused on p53 tumor suppressor gene and these studies had shown that disruption of p53 pathway through mutations, loss of heterozygosity ( LOH ) or interaction with viral proteins, as the most frequent alterations in oral cancer. Although p53 changes had been detected (Murti et al 1998) in premalignant lesions also, the applicability of p53 as a promising predictor could not be defined. In an earlier Indian study, Ralhan et al (2006) attempted to elucidate the relationship between the expression of retinoic acid receptors and cell cycle regulators such as p53, p21 and p16. This study revealed expression of retinoic acid receptors RAR-α, β, γ to be altered in premalignant lesions. Moreover, positivity of RAR-α in the epithelium was frequent in the phenotype significantly associated with pre-cancers that underwent malignant transformation.

Deletions in the retinoblastoma (RB1) gene were reported (Sabbir etal, 2006) to be infrequently altered in head and neck SCC patients and was especially associated with later stages in head and neck SCC development in Indian patients. Tripathi et al (2003) and Ghosh et al (2010) also demonstrated low frequency of RBI deletion in dysplastic lesions but deletion frequency was significantly increased to stage I and II tumors.

Another group of Indian researchers demonstrated that alterations ( deletions / methylation ) of LIMD1 gene, a candidate tumor suppressor gene located at 3p21.3, was significantly associated with mild dysplastic lesions of head and neck cancers. In dysplastic lesions, LIMDI mutations were less frequent than deletion and methylation .deletion and methylation of LIMDI was suggested as early event in oral carcinogenesis. LIMDI was reported to inhibit cell growth and metastases partly mediated through either an interaction of its N-terminal LEM domain (amino acid 18 - 68) with barrier – to- auto integration (BAF) , a component of SWI/ SNF chromatin – remodeling protein , or through interaction of its part of praline –serine rich domain (amino acid 326-608) with C-terminus of retinoblastoma protein pRB (amino acid 763-928) followed by transcriptional repression of E2F target genes( Sharp et al 2008)

Moreover Ghosh et al (2010) also demonstrated that co- alteration of both RBI and LIMDI was high in the late stage III and IV of head and neck lesions. Furthermore, patients with both LIMDI and RBI alterations showed worse prognosis and absence of RBI alterations did not change patients’ survival considerably. This suggests that RBI inactivation might have some synergistic impact in HNSCC development. Ghosh etal, (2010) proposed that the reduced level of LIMDI in oral cancer cells might be destabilizing the PRB-E2F interaction and chromatin remodeling complex resulting in deregulation of cell cycle.

The research data from this group demonstrated LIMDI inactivation as a primary event in HNSCC development and implicated LIMDI as a susceptible gene for HNSCC development .Furthermore LIMDI alterations, alone or with RBI alterations could be considered as an important prognostic marker in this cancer.

Worldwide, several other studies also had reported molecular alterations in oral cancer. Most of these studies highlighted alterations in genes/pathways which control cellular signaling, cell cycle, apoptosis, genomic instability, cytoskeleton, and angiogenesis to be significantly associated with progression of potentially malignant disorders of OSCC. However, these genetic tumors markers have so far not gained any use in routine diagnosis and their utility in the prediction of risk of malignant transformation remains unclear. But these studies have clearly indicated that multiple genes/ pathways are involved in the progression from normal to metaplastic / dysplastic and subsequently to cancer

Epigenetics

Epigenetics is being recognized as an increasingly important area of research that involves an understanding of the molecular mechanisms that influence the phenotypic outcome of the genome without alteration of the DNA sequence

Most of the genetic alterations associated with oral cancer development are the result of direct damage to the genome. Additionally, there are other mechanisms of heritable somatic changes in gene expression that do not require direct alteration of the DNA sequence itself. By the addition or subtraction of methyl groups (methylation) without a change in the base composition, the DNA molecule can be modified. So also histones,the structural proteins found in close association with DNA can be modified(histone modification) by acetylation ,methylation or ubiquitylation.these non-DNA encoded modifications are known as epigenetic alterations

, can result in heritable changes in gene expression that are clinically significant including cancer development. Few oral cancer research groups in India including oral cancer research at RCC are studying the epigenetic changes in oral cancers with the hope of exploring their potential utility in oral cancer diagnosis, staging surveillances and clinical application

The concept of inherited epigenetic susceptibility to tobacco related cancers is certainly of interest which may offer an interesting avenue for molecular staging. Identification of these individuals might allow more focused and hence, more cost effective prevention strategies in OSCC.

Oral cancer screening

In a south Indian population, oral cancer screening employing visual inspection was reported (Sujha etal 2009)as cost effective method for early detection of oral cancer which can significantly reduce the associated high morbidity and mortality. An analysis of oral cancer incidence from 1990 to 2005 in Chennai, India, has revealed the benefit of public health education and interventions demonstrating a significant parallel reduction in oral cancer incidence.

Future prospective

the incidence of tongue cancer has been increasing during the last 10 years ,especially among young adults, less than 40 years ,who never smoke or chew tobacco and never consumed alcohol .in view of the rapidly increasingly incidence which is a matter of alarming concern. Few Research centres in India with International collaboration, are studying the possible disease pathways especially the role ofHPV16 and 18 and oral sex practices and to

elucidate the reasons for this phenomenon.

Further studies on the sequence of genetic alterations associated with oral cancer will help in understanding the molecular basis and natural history of oral cancer development. Undeniably embracing new high throughput genomic technologies including microarrays, array comparative genomic hybridization, SNP arrays, methylation microarrays,gene expression

arrays, proteomics mitochondrial arrays and micro RNA arrays offers exciting opportunities for advances in the broad are of oral carcinogenesis .exploration of oral cancer biomarkers in biofluids such as saliva and serum are other promising approaches

Advances in next generation sequencing and genomic technologies are unlocking the biology of disease in ways not previously possible, leading to a paradigm change in target finding, drug development and patient treatment.

India is participating in International Cancer Genome Consortium(ICGC),with oral cancer as the site for research .Focusing on the gingiva-buccal cancer, the goal is to obtain a comprehensive description of genomic,transcriptomic and epigenomic changes in 50 different tumor types and/or subtypes which are of clinical and societal importance across the globe. The lead institutions who are part of this project are National Institute of Biomedical Genomics (NIBMG) where most of the genomics work will be carried out, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Mumbai where most of the patient characterization, tissue collection and molecular genomic profiling will be done. The project is funded by Government of India through the Department of Biotechnology.

According to Dr.PPM that since oral cancer is highly prevalent in India with genomic susceptibilities and environmental triggers (such as tobacco chewing and smoking) an understanding of the genomic factors and their interaction with environmental triggers will help reduce disease burden in the population by identifying individuals at high risk before the onset of oral cancer and aggressive modulation of their life styles to prevent environmental triggers.

Genome wide analysis may soon be capable of identifying not only genomic patterns associated with varying levels of cancer risk, but also the environmental susceptibilities that result from these genomic patterns. It is hoped that growing understanding of the genetic and environmental factors involved in oral carcinogenesis, will allow the emphasis of cancer medicine to shift from the therapy of established oral cancer to the prevention of oral carcinogenesis.

References

- Hunter K D, Parkinson E K Harrison P R. Profiling early and neck cancer, nat res cancer 2005;5:127-135

- Brakhuis BJ , Brakenhoff RH, humans R Head and neck Cancer: molecular carcinogenesis.Ann Oncol 2005 ;16(2):249-250

- Tripathi A, Dasgupta S, Roy a etal . sequential deletions in both arms of chromosomes ( are associated with the development of head and neck squamous cell carcinomain Indain patientsJ expt clinn cancer res 2008;22(3):289-297.

- Chakraborty SB, Dasgupta S, Roy A etal . different head and neck squamous cell carcinoma from Indian patints . cancer genetics and cytogenetics,2003;145:1-9

- Ghosh S, Ghosh A, Maiti GP etal . alterations of 3p21.31 tunour suppressor genes in head and neck squamous cell carcinoma.correlation with progression and prognosis int J. cancer 2008; 123(11) ;2594-2604

- Ghosh S, Ghosh A, Maiti GP etal LIMDI is more frequently altered than RB1 in head and neck squamous cell carcinoma: clinical and prognostic implications: molecular cancer2010;9;58-70

- Sabbir G, roy A, Mandol S, dam a, Roychaudary S, Panda CK. Deletion mapping of chromosome 13Qin head and neck squamous cell carcinoma in Indian patients:correlation with prognosis of the tumour . Exp pathol.2006;87:151-161

- Sharp TV , Munoz F, Bourboutia D etal . LIM domains containing protein ! ( LIMDI) a tumour suppressor encoded at chromosome 3p21.3 binds pRB and represses E2 F Driven transcription proc. Natl Acad Sci 2004 ;101: 16531-16536

11. Role of dental surgeons in Prevention and

Control of oral cancer

Oral cancer is a preventable cancer. If detected early and managed properly, it is mostly curable. Excellent pain relief and palliative care can be given to the terminally ill. But the paradox is that even today, thousands in India develop oral cancer and majority of them die miserably of this disease. It is high time for the Dental Profession to review what they can offer for the prevention and control of oral cancer.

Primary prevention of Oral Cancer

There are three strategies for primary prevention.

(1) Avoidance or reduction of risk factors
(2) Chemoprevention
(3) Avoidance of genetic risk.

The general dentists have ample opportunities in all these areas. The most important etiological factors for oral cancer are habitual consumption of tobacco, arecanut and alcohol. The strategies for the control of these habit forming substances are

(1) creation of awareness about their hazards, (ii) legislation to restrict the production and sale, (iii) advocacy activities to make their consumption an unaccepted social practice & (iv) establishment of cessation clinics. The General Dental practitioner can act on all areas. On an individual basis when an arecanut/tobacco/alcohol habitué is identified during oral examination, that person should be made aware about the hazards of the addiction and advised to stop tobacco and alcohol consumption. If needed, assistance may be given to quit the habit. The Dentist can function as a resource person in anti-tobacco activities organized by Non-Governmental Organisations and Community Groups like the Residents’ Association. Dentists should join hands with Governmental programmes for tobacco control.

Chemoprevention in the process by which cancer is prevented or delayed from developing by the administration of simple substances to high risk groups. Dental surgeons are in very good position to offer chemoprevention advices to high risk groups. Common chemopreventive agents tried with variable success are vitamin A, synthetic retinoids, carotenoids, curcumin, selenium and spirulina.

Early detection of Oral Cancer ( Secondary Prevention)

Majority of oral cancers arise from pre existing precancerous states. So the best strategy of early detection will be detection of oral precancers. It will be considered as negligence by the dentist if a cancer or pre cancer is missed during routine oral examinations and treatment.

Early oral cancer is asymptomatic. A patient with asymptomatic oral cancer should be emphatically told the fact that one should get state of the art treatment without time loss lest the cancer will become incurable and the treatment cost will escalate heavily. Complications of treatment will be much more in advanced cases. Patients with precancer also should be told about the high probability of such benign lesions becoming malignant and the usefulness of proper habit intervention to prevent cancer. Dental students should be properly trained in the diagnosis, evaluation, treatment and follow up of precancers.

Cases of precancers showing clinical signs of malignant transformation and clinically frank malignancies should be biopsied. Adequate training should be given in taking biopsies and sending the specimen properly to a pathology laboratory. When a case is histopathologically confirmed, that patient should be referred to an appropriate oral cancer treatment centre without losing valuable time.

Dental surgeon is a member of oral cancer management team in all modern cancer centers. Patients considered for radiation should undergo preparative procedures like extraction of badly decayed teeth, endodontic and conservative procedures in carious teeth, improvement of oral hygiene and fluoride application, prior to radiation. The dentist can make biteblocks, protective shields, and positioning devices to direct the radiation beam. They can also make moulds for positioning radioactive needles and place polythene catheters for after loading brachytherapy. During radiation, patient should be monitored and treated to prevent/reduce complications of radiation. Prosthetic rehabilitation is another area where dentist can improve the quality of life of a surgically managed patient.

Palliative care (Tertiary prevention)

Among all the specialists in medical profession the dental surgeon is the best option to examine and treat oral cancer patients in terminal stages. With a short training, dentists can give neurolytic blocks, manage dysphagia, dyspnoea, bleeding and treat pain and other distressing symptoms very effectively.

The training of Dental Surgeons should be in the following areas of palliative care.

1. Pain management using the WHO step ladder principle
2. Giving nerve blocks
3. Management of fungating and foul swelling ulcers
4. Management of varying grades of xerostomia using home-made synthetic saliva.
5. Management of opportunistic infections.
6. Nutrition and dietary counseling of compromised patients.
7. Monitoring for radiation caries and osteoradionecrosis and management of these.
8. Preparing the patient to face death with courage
9. Supporting the family to face bereavement boldly
10. Knowledge about alternate systems and other methods of palliative care.

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