|Year : 2021 | Volume
| Issue : 2 | Page : 189-194
Evaluation of serum immunoglobulin (IgG, IgM, IgA) in oral cancer patients – A case control study
Vivek M Tarsariya1, Nilesh Raval2, Dhaval N Mehta3, Mukesh K Asrani2, Vijay K Asrani2, Kaushik S Barot4
1 Dental Department, General Hospital, Godhra, Gujarat, India
2 Department of Oral Medicine and Radiology, Karnavati School of Dentistry, Uvarsad, Gandhinagar, Gujarat, India
3 Department of Oral Medicine and Radiology, Narsinghbhai Patel Dental College and Hospital, Visnagar, Gujarat, India
4 Department of Pediatrics, Shantabaa Medical College, Amreli, Gujarat, India
|Date of Submission||22-Nov-2020|
|Date of Decision||04-Feb-2021|
|Date of Acceptance||01-Apr-2021|
|Date of Web Publication||23-Jun-2021|
Dr. Vivek M Tarsariya
Madhuram Hospital, Hathsani Road, Savarkundla - 364 515, Amreli, Gujarat
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Very few studies have been done to evaluate the level of serum immunoglobulins (IgG, IgM, and IgA) in patients with oral cancer as tumor markers. Aims and Objectives: The aim of this study was to estimate the serum immunoglobulins level (IgG, IgM, and IgA) in oral cancer patients and its comparison with control groups and whether these values can be used to predict the severity of disease or not. Materials and Methods: A total of 30 patients with different clinical stages oral cancer and 30 healthy controls were selected at random and subjected for analysis of serum IgG, IgA, and IgM. Statistical methods used were the mean, standard deviation and t test. Results: Significantly elevated levels of all the immunoglobulins was observed in oral cancer patients when compared with the control group and levels were increasing with clinical stages (P < 0.05). Conclusion: All these immunoglobulins are indicative of tumor burden or transformation of malignancy in higher stage and might be used as prognostic indicators in oral cancer.
Keywords: IgA, IgG, IgM, oral cancer, serum immunoglobulin, tumor marker
|How to cite this article:|
Tarsariya VM, Raval N, Mehta DN, Asrani MK, Asrani VK, Barot KS. Evaluation of serum immunoglobulin (IgG, IgM, IgA) in oral cancer patients – A case control study. J Indian Acad Oral Med Radiol 2021;33:189-94
|How to cite this URL:|
Tarsariya VM, Raval N, Mehta DN, Asrani MK, Asrani VK, Barot KS. Evaluation of serum immunoglobulin (IgG, IgM, IgA) in oral cancer patients – A case control study. J Indian Acad Oral Med Radiol [serial online] 2021 [cited 2021 Jul 29];33:189-94. Available from: https://www.jiaomr.in/text.asp?2021/33/2/189/319068
| Introduction|| |
Cancer is the Greek word “Karkinos”, meaning crab, denoting how carcinoma extends its claws like a crab into the adjacent tissues. Cancer is the second and third most leading cause of mortality in economically developed and developing countries, respectively.
Oral squamous cell carcinoma (OSCC) is the most frequent malignancy in the mouth, accounting to 90–95% of all oral malignant lesions. It is an important cause of morbidity and mortality worldwide with an incidence rate that varies widely by geographic location.,
In India, cancer is the sixth leading cause for death and oral cancer accounts for 30–40% of all cancers in contrast to 2–4% in other western countries and is the most prevalent cancer in males and the third most prevalent in females. In India, there is a striking incidence of oral cancer where tobacco chewing with betel nuts and reverse smoking is practiced., Tongue, lower lip and floor of the mouth are most affected sites. It affects mostly in the fifth to eighth decades of life, who is a tobacco chewer and/or a smoker.
There are multiple risk factors for the development of oral cancer. The high incidence is attributed to the habits of chewing betel leaf with arecanut with or without tobacco, betel quid chewing, smoking, alcohol, malnutrition, etc. It is important to note the frequency per day and duration of the habit that patient had the habit in years which is called Habit Index. Habit Indexis calculated by multiplying frequency of habit per day and number of years of habit.
The term tumor marker is applied to indicate the risk, presence, status, or future behavior of oral cancer. Immunoglobulins are proteins of animal origin endowed with known antibody activity and for certain other proteins related to them by chemical structure and have antigenic specificity. Based on physiochemical and antigenic differences, five classes of immunoglobulins have been recognized – IgG, IgA, IgM, IgD, and IgE. The aim of the study was to estimate the serum immunoglobulins (IgG, IgM, IgA) level in oral cancer patients and its comparison with control groups and weather these values can be used to predict severity of disease or not particularly in oral cancer patients of Gandhinagar region of Gujarat, India.
| Materials and Methods|| |
This study was performed on patients attending outpatient department of Oral Medicine and Radiology of a dental college, Gandhinagar, Gujarat for 2 years. Before conducting study, research proposal was submitted to institutional ethics committee and permission to conduct the study was obtained with reference no. KSD/PG/Ethics/2010-11/08, dated 24/08/2010. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1964 and later versions.
To determine sample size, a pilot study was conducted among 10 patients. The mean serum IgG in oral cancer was 16.56 ± 2.43, in control group was 14.72 ± 2.65 having mean difference of 1.84. Considering the mean difference of 1.84, 80% power of study, ratio of sample size (group 1/group 2) as 1 and 95% confidence interval and the alpha level used in the study was 0.05, the sample size of 30 was obtained in each group. Hence, total sample size of 60 was considered for the final study. The sample was selected using random sampling technique with an age range of from 18 to 70 years [Table 1]. 30 patients (21 males and 9 females) with different clinical stages of oral cancer (stage I––4, stage II––4, stage III––13, and stage IV––9) and 30 healthy individuals (14 males and 16 females) without any habit or systemic illness were included [Figure 1]. Most recent staging system by the American Joint Committee on Cancer (AJCC) TNM (Tumor Node Metastasis) staging system for oral cancer (2002) was utilized.
|Figure 1: Total number of male and female patients in oral cancer and control group|
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Any patient having oral cancer (clinically and histopathologically confirmed) age more than 18 years and without any systemic illness.
- Patients having any major systemic illness like diabetes, hypertension or under medication for any other systemic condition.
- Mucosal lesions other than oral cancer.
- Any patient who previously undergone any treatment of oral cancer.
- Patients who are not willing to participate in the study.
After written informed consent was taken from participant, thorough history was taken and all patients were examined by using mouth mirror and probe under artificial light taking universal precaution. All patients with oral cancer were confirmed with histopathological report after taking punch biopsy. Data were collected in a specially designed proforma. Blood was collected from the mid cubital vein. The area was made aseptic by using absolute alcohol and by using bi - ended needle with connector and 4 ml of blood was drawn directly into yellow capped sterile vacuumed tubes which contained gel plus clot activator. The blood was allowed to clot for 60 minutes and then centrifuged at 2000 rpm for 10 minutes. Serum was separated with use of pipette and stored in a separate container. The samples were stored in a deep freezer at –20°C until analyzed. Only fresh samples were taken for assay, hemolyzed samples were discarded. The estimation of serum immunoglobulins [IgG, IgM, IgA] was done by the Nephelometric technique in automatic analyzer (Olympus AU 400).
After collection of data and results of immunoglobulin values of all patients, data were tabulated for statistical analysis. The Statistical Package for Social Sciences (SPSS) software program, version 15.0 for Windows (SPSS, Chicago, Illinois) was used for the statistical analysis and mean, standard deviation calculated and t test applied. For all tests, a value of P < 0.05 (5%) was considered statistically significant.
| Results|| |
We observed significantly elevated levels of Immunoglobulins (IgG, IgM, and IgA) in all the oral cancer patients when compared to control groups. The mean value of serum IgG of oral cancer group was 16.218 ± 2.505 g/L and for control group 11.712 ± 1.766 g/L, the mean value of Serum IgM of oral cancer group was 1.658 ± 0.677 g/L and for control group 0.702 ± 0.309 g/L mean value of Serum IgA of oral cancer group was 3.280 ± 1.209 g/L and for control group 2.101 ± 0.646 g/L and it was statistically significant (P < 0.05) [Table 2].
|Table 2: Comparison of mean IgG, IgM, IgA between oral cancer and control groups|
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It was seen that increased levels correlated well with clinical stages of malignancies. In oral cancer, the mean value of Serum IgG in stage 1 was 12.986 g/L, stage 2 had 15.812 g/L, stage 3 16.144 g/L and stage 4 had 17.941 g/L [Figure 2]. For Serum IgM, Mean value of stage 1 was 1.007 g/L, stage 2 was 1.555 g/L, stage 3 was 1.652 g/L and stage 4 had mean value of 2.000 g/L [Figure 3]. For Serum IgA, stage 1 had mean value of 2.572 g/L, stage 2 had 3.040 g/L, stage 3 had 3.259 g/L and stage 4 had mean value of 3.732 g/L [Figure 4].
|Figure 2: Mean values of IgG increase with clinical stages of oral cancer|
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|Figure 3: Mean values of IgM increase with clinical stages of oral cancer|
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|Figure 4: Mean values of IgA increase with clinical stages of oral cancer|
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| Discussion|| |
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 was 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.,
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 tumor suppressor genes and chromosomal changes. Defect in host's immune system with an 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.
Best way to reduce incidence and mortality of oral cancer is prevention and early detection. The immunological method is one of the many methods for early detection of oral cancer. The tumor marker concept has evolved and new tumor markers are frequently introduced into clinical practice over the years but so far none meets all the criteria of an ideal tumor marker.
Biomarkers are special molecular signature of each cell, identified by its serum levels or actions like the abilities of genes or proteins to execute their functions. For objective measure of assessment of normal biological or pathogenic processes, or pharmacological responses to a therapeutic intervention, biomarkers can be utilized, which includes all diagnostic tests, imaging, and any objective measure of health status of an individual. Biomarkers are subject to dynamic modulation, expected to improve understanding of drug metabolism, action, efficacy, and safety. Biomarkers also facilitate molecular definition of diseases, provide information about the course of disease, and anticipate response to therapies.
Malignant cells show a broad spectrum of genetic alterations leading to disturbances in molecular pathways regulating cell growth, survival, and metastasis. Specific type of tumor, signs which are observed in majority of patients, can be utilized as biomarkers for detection and developing targeted therapies, in addition to predicting responses to various treatments.
Immunoglobulins are produced by plasma cells and lymphocytes and found in body fluids or tissues such as urine, spinal fluid, milk, saliva, tears, lymph nodes and spleen and constitute 20-25 percent of the total serum proteins. It serves as a specific link between epitopes on tumor cell antigens and the host-effectors cells.
In serum, the predominant immunoglobulin belongs 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. Hu 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. In contrast, Neuchrist et al. found no significant difference between tumor 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 the neoplastic process.
Elevated levels of IgG show 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 posttherapy. A 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) is expressed on the surfaces of B cells and constitutes approximately 10% of normal serum immunoglobulins. The B-cell system of the marrow stem cells first gives rise to IgM-producing cells in humoral immunity. So IgM class is the first antibodies to appear in the serum after primary exposure to an antigen. 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. Hu et al. Parveen S, et al. Shah N, et al. and Veltri et al. 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 control level. This is probably due to the fact that the selective clones of cells producing different types of immunoglobulins respond to the malignancies in different ways.
Serum IgA is secreted in milk, colostrums, saliva, tears, and secretions of GIT and approximately 1/6th that of IgG. In our study, increased levels of mean IgA values were found among oral cancer patients when compared to control groups which were consistent with studies by Parveen S, et al. Veltri RW, et al. Katz AE, et al. Scully C, et al. Vijay Kumar T, et al. and Mishra R, et al., Schantz SP, et al. showed 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 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.
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 the highest values of IgA in patients with advanced disease. 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.
A 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 showed 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 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 twofold 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 tumor antigen/residual disease and appears to be directly related to tumor 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., Higher levels of these parameters may indicate poor prognosis and decrease survival rate. Therefore it is suggested that serial monitoring of Immunoglobulin could be used to know the prognosis, tumor burden, or survival rate of patients.
Limitations and future prospects
Further studies are needed to evaluate the exact role(s) of serum immunoglubulins in oral cancer as tumor marker and its levels with stages of cancer and patient's prognosis after treatment also. Furthermore, research studies with a larger sample size and a long-term assessment in the form of a longitudinal study are needed involving government and private hospitals to know the actual estimate the prevalence of disease. Considering these factors and the fact that this was a preliminary study done on a small scale, we cannot generalize these results to other communities.
| Conclusion|| |
Clinical oncology is poised to enter a new era in which oral cancer detection, diagnosis, and treatment will be guided increasingly by the molecular attributes of the individual patient, acquired from several different sources like diseased tissue, host cells/tissues that influence tumor behavior and body fluids. The biomarkers will not only help the detection and diagnosis, but also answer fundamental questions about the biological behavior of tumors, resistance to therapy and sensitivity to therapy. Higher levels of immunoglobulins in oral cancer are indicative of tumor burden or transformation of malignancy in higher stage and might be used as prognostic indicators.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]