Chewing areca nut with betel quid is practiced since two millennia. Four centuries back tobacco introduced and currently all areca nut chewers use it in combination. With the advent of 'pan masala' areca nut chewing has received a boost in last couple of decades. Due to easy availability, marketing, stress relieving effects, status trends and peer pressure, habit of smoking or smokeless tobacco and chewing betel nut in form of Panmasala or gutkha increased in youngsters which lead to premalignant and malignant diseases of oral cavity.[9, 10]
Prevention and early detection is the best way to reduce incidence and mortality of oral cancer. There are many methods of early detection of oral cancer and immunological method is one of them.
Response to cancer is very complex process as it mainly depends on immune status of person, extent and severity of disease and response to treatment and resistance development plus effects of oncogenes or tumour suppressor genes and chromosomal changes. Defect in host’s immune system with increase in age might be reason behind occurrence of cancer, hence research in early cancer diagnosis has led to discovery of many immunological markers that contribute considerably to supplement the established method of diagnosis.
The tumour marker concept has evolved and new tumour markers are frequently introduced into clinical practice over the years but so far none of them meet all the criteria of an ideal tumour marker.
Biomarkers are unique molecular signature of each cell, which are identifiable by its levels or activities like the abilities of genes or proteins to perform their functions. So, for objective measure of evaluation of normal biological or pathogenic processes, or pharmacological responses to a therapeutic intervention, biomarkers can be used and it includes all diagnostic tests, imaging, and any objective measure of health status of an individual. Biomarkers are subject to dynamic modulation, and are expected to enhance our understanding of drug metabolism, drug action, efficacy and safety. These can also facilitate molecular definition of diseases, provide information about the course of disease and predict response to therapies. 
Malignant cells display a broad spectrum of genetic alterations leading to disturbances in molecular pathways regulating cell growth, survival and metastasis. With a specific type of tumour, manifestation of such changes seen in majority of patients, these can be used as biomarkers for detection and developing targeted therapies, besides predicting responses to various treatments. 
Immunoglobulins constitute 20–25 percent of the total serum proteins and are synthesized by plasma cells and also by lymphocytes and also found in other body fluids or tissues such as urine, spinal fluid, milk, saliva, tears, lymph nodes and spleen. Immunoglobulin serves as a specific link between epitopes on tumour cell antigens and the host-effectors cells. Many studies done for specific immunoglobulin response in oral cancer.
In serum the predominant immunoglobulin belong to IgG class. It is the only maternal immunoglobulin that is normally transported across the placenta and provides natural immunity in the newborn. In our study IgG was significantly elevated among the oral cancer compared to controls. The values of Serum IgG were increased from stage I to stage IV. Studies by Balan et al, Kohli et al, De-en et al and Parveen S et al have shown significant elevation of IgG in oral cancer stages. The results of these studies with respect to IgG and gradual increase in their levels with stages of malignancy were consistent with our study.[4,14−16] In contrast, Neuchrist et al found no significant difference between tumour and controls.
The elevation of IgG levels in oral cancer patients may be due to dependencies of IgG on the intensity of the antigenic stimulation and functional capacity of the antibody producing mechanism. Consequently, the increase in IgG in this group of patients could be due to intensive antigenic stimulation that is possibly due to neoplastic process.
Elevated levels of IgG demonstrate an immune response which is helpful in antibody dependent cytotoxic–cell killing of tumor cells, however, tumor cell can release inhibitory substances and produce a blocking factor (probably IgG2) to protect them from attacks by cytotoxic antibodies, and can also form complexes which act as blocking factors and further weaken cellular immunity. In contrast, Tsavarius found that the group of patients having increased IgG and perhaps IgM levels showed a longer time for progression of disease and prolonged overall survival time.
Banerjee S et al in their study of humoral response in malignancies with special reference to the effect of radiotherapy found the mid therapy fall of IgG and regain during post therapy. Possible explanation for midtherapy fall might be due to temporary exhaustion of regional lymphatic system by radiotherapy, regain probably due to stimulation of antibody response secondary to products of necrosis after application of radiotherapy.
Serum immunoglobulin (IgM) constitutes approximately 10% of normal serum immunoglobulins. It is the most common immunoglobulin expressed on the surfaces of B cells. In humoral immunity the B cell system of the marrow stem cells first give rise to IgM producing cells. So the first antibodies to appear in the serum after primary exposure to an antigen are of IgM class. IgM producing cells serve as the progenitors of other IgM producing cells and give rise to IgG progenitors.
The serum IgM levels are often increased in patients with oral cancer. Our study also shows higher values of IgM in the patients with oral cancer when compared to controls, which is in agreement with studies done by Balan et al, Kohli et al, De-en et al, Parveen S et al, Shah N et al and Veltri et al.[4, 14–16, 20, 21] Khanna NN et al observed increased levels of IgM in cancer patients correlated with the clinical stages. In contrast, Banerjee S et al found decreased serum IgM than that of the controls level. This is probably due to the fact that the selective clones of cells producing different types of immunoglobulins are responding to the malignancies in different ways.
Serum immunoglobulin (IgA) is approximately 1/6th that of IgG. It is efficiently secreted in milk, colostrums, saliva, tears and secretions of GIT. In our study, increased levels of mean IgA values were found among oral cancer patients when compared to control groups which was consistent with studies by Parveen S et al, Veltri RW et al, Katz AE et al, Scully C et al and Vijay Kumar T et al.[16,20,23−25] Schantz SP et al demonstrated significant difference in only IgA titers between cancer patients and controls.
Kohli GS et al found higher level of all three immunoglobulins than the control group in which levels of IgA being more than that that of IgG and IgM. Khanna et al reported a significant increase in IgA as well as IgM levels, whereas Increased IgA and IgG levels were observed in oral cancer by Brown et al and Gupta et al.[27, 28]
Higher levels were associated with advanced disease rather than early primary disease. We observed increased IgA levels with progression of oral cancer which was consistent with findings of Balan N et al and Schantz SP et al who observed highest values of IgA in patients with advanced disease.[4, 26] Serum concentrations of IgA were increased in oral cancer patients as IgA is the predominant immunoglobulin secreted into mucosal surface of the nose, mouth, stomach, intestine, lungs, tears and colestrum. Assuming a local immune response of the mucosal immune system to malignancies there could be an increased level of antigenic stimulation and cancer of such organs resulting in increased synthesis of IgA which is reflected in serum level.
Previous study conducted by Susal C et al in head and neck squamous cell carcinoma patients for IgA-anti-Fab autoantibody activity and it was higher in carcinoma patients than the normal healthy controls and stage IV patients had significantly higher IgA-anti-Fab than the stage I patients. Similarly, Lorenz et al found that higher IgA anti-Fab activity in stage IV compared to stage I and II demonstrated highest values in patients who died within 6 months after final diagnosis suggesting an association between autoimmunity and final disintegration of physiologic body functions.
Schantz SP et al found that elevated IgA blood levels reflect the autoimmune nature of cancer, an immunologic state defined by its tumor–promoting capacity, poor prognosis and higher probability of recurrent disease than those with normal IgA values. Brown AM et al reported two fold increase of serum and salivary IgA in primary oral and laryngeal carcinoma compared to controls. A follow up after radiotherapy confirmed a drop in salivary IgA with cure, and a spike with recurrence. Persistent elevation in advanced diseases and elevated levels after therapy may be due to persistence of tumour antigen / residual disease and appears to be directly related to tumour burden. De Souza et al evaluated serum and salivary IgA by two different methods in patients of cancer of mouth and oropharynx, result showed no difference between patients and normal subjects which was not matched with our result.
Increased level of immunoglobulins may reflect local infiltration of plasma cells adjacent to the growth and superadded infection in oral cancer may further increase immunoglobulin levels. Increased levels of immunoglobulins with advanced stage of oral cancer are indicative of an adverse prognosis.[14, 16] Higher levels of these parameters may indicates poor prognosis and decrease survival rate. Therefore it is suggested that serial monitoring of Immunoglobulin could be used to know the prognosis, tumour burden or survival rate of patients.