|Year : 2012 | Volume
| Issue : 6 | Page : 116-122
Serum circulating immune complexes as prognostic indicators in premalignant and malignant lesions of oral cavity during and following radiotherapy
Shalu Rai, RN Mody
Department of Oral Medicine and Radiology, Institute of Dental Studies and Technologies, Modinagar (U.P), India
|Date of Web Publication||24-Jan-2012|
Professor and Head Department of Oral Medicine and Radiology Institute of Dental Studies and Technologies, Modinagar (U.P)
Source of Support: None, Conflict of Interest: None
Aim: The aim of the study has been to quantitatively estimate and compare the circulating immune complexes (CIC) in pre-malignant and malignant lesions of oral cavity and to serially monitor the CIC levels in oral squamous cell carcinoma (SCC) during / following radiotherapy as to assess the status of the disease and to understand the prognostic significance.
Materials and Methods: The present study was carried out on 90 individuals divided into three groups and CIC was estimated by spectrophotometric method using polyethylene glycol (PEG) precipitation method. The mean CIC level was determined in each group and was correlated with the degree of differentiation and degree of dysplasia in malignant and pre-malignant group respectively. The effect of radiotherapy on the level of CIC was studied after 2400 rad and after one week of 4500 - 5000 rad.
Results: It was observed that the mean CIC level in the control group was significantly lower (59.56 ± 8.11) when compared with the pre-malignant group (75.93 ± 12.89) and malignant group (92.66 ± 13.96). Among the pre-malignant group, leukoplakia had the highest mean CIC level followed by lichen planus and oral submucous fibrosis (OSMF), suggesting its greater malignant potential. No correlation could be established between degree of differentiation and degree of dysplasia with the CIC levels in malignant and premalignant groups respectively. There was a definite decrease in the mean CIC levels in patients undergoing radiotherapy.
Conclusion: The pretreatment value of CIC can be used as a prognostic indicator. A high CIC level would probably indicate a poor prognosis.
Keywords: Circulating immune complexes, oral cancer, premalignant lesions, radiotherapy
|How to cite this article:|
Rai S, Mody R N. Serum circulating immune complexes as prognostic indicators in premalignant and malignant lesions of oral cavity during and following radiotherapy. J Can Res Ther 2012;8, Suppl S2:116-22
|How to cite this URL:|
Rai S, Mody R N. Serum circulating immune complexes as prognostic indicators in premalignant and malignant lesions of oral cavity during and following radiotherapy. J Can Res Ther [serial online] 2012 [cited 2020 May 26];8:116-22. Available from: http://www.cancerjournal.net/text.asp?2012/8/6/116/92225
| > Introduction|| |
Simply holding knowledge about a factor does not automatically translate into a change in behavior, but having correct and current knowledge or information is necessary to make intelligent decisions. The importance of early detection of oral cancer is well understood and cannot be overemphasized.
Generally the assessment of the likely behavior of precancerous lesions and established carcinomas still relies heavily on histological examination. This process may induce fear in patient as it involves surgical removal of tissue and associated discomfort. This has necessitated the invention of specialized but simple laboratory techniques which provide vital information about this deadly disease. Over the past few decades, there is an increase in the awareness of the role of circulating immune complexes (CIC). Recent advances in the field of CIC, tumor progression, drug resistance, tumor cell heterogenicity and metastasis have led to the development of non-specific immunotherapeutic modalities. 
Oral submucous fibrosis is a chronic diseases that affects the oral mucosa as well as the pharynx and the upper two third of the esophagus.  There is substantial evidence that lends support to the critical role of areca nuts in the etiology behind submucous fibrosis. , There is also evidence of genetic predisposition of importance for the etiology behind submucous fibrosis. Oral complications are more commonly observed in lips, buccal mucosa, retromolar area and soft palatal mucosa. The global incidence of submucous fibrosis is estimated at 2.5 million individuals. , The prevalence in Indian population is 5% for women and 2% for men.  The malignant transformation in patients with OSMF ranges from 3 to 6%. 
The development of oral leukoplakia as premalignant lesion involves different genetic events along with the use of various forms of tobacco.  The comprehensive global review points at a prevalence of 2.6%.  Malignant transformation of leukoplakia ranges from 3 to 20%.  In Indian house to house survey, 80% of oral cancer were reported to be preceded by oral precancerous lesions or conditions. ,
The pathogenesis of oral lichen planus is still unknown.  During recent years, it has become more evident that the immune system has the primary role in the development of this disease. , In the literature, different prevalence figure for oral lichen planus has been reported and vary from 0.5 to 2.2%.  The incidence of malignant transformation of lichen planus is low and presumably does not exceed an incidence of 0.2% per year. 
|Figure 1: Mean CIC levels in control group and in patients with premalignant and malignant lesions|
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Cancer is one of the most formidable health problems facing mankind today. Despite half a century of intensive effort throughout the world, cancer still remains an enigma. The "Ramayana", one of the classical manuscripts of ancient Indian mythology (2000 BC), presents the earliest available record to identify malignant tumor as a disease entity. Most of the oral cancer patients initially present with premalignant lesions mainly oral submucous fibrosis, leukoplakia.
In India, cancer is the sixth leading cause of death and oral cancer is the most commonly occurring malignancy, amounting to about 40% of all malignancies in contrast to 2-4% in western countries.  The high incidence of oral cancer and oral precancerous lesion in India has long been linked with the habit of chewing tobacco in various forms which differ from region to region. ,, Squamous cell carcinoma comprises of 90-95% of all oral malignancies. 
The concept of "immunologic surveillance" proposes that the host recognizes a tumor as foreign and then mounts a protective immune response against the tumor. There is clear evidence of immunological influence on the development of malignancy, but whether a tumor develops because of a failure of recognition mechanism or a breakdown of the immune response is unclear. 
Potentially premalignant lesions are more liable to develop into cancer than similar intact tissue, as judged from clinical and pathologic conditions. 
Although the pathogenesis of lichen planus and leukoplakia remain to be proven, association of immune defense mechanism especially in patients with lichen planus has been studied.  Patients with lichen planus show various immunological derangements such as influx of T4 (helper) and T8 (suppressor) cells at the ratio of 2:1 to 3:1, increase in number of Langerhans cells and macrophages.  The presence of immunoglobulins (IgG, IgA and IgM) and complement in patients with oral submucous fibrosis indicate the role of active immune phenomenon at work. ,, Rajendran et al, has reported a depression in the cell mediated and humoral immunity in premalignant lesions of oral cavity. 
Cell mediated immune response are impaired in patient of head and neck cancer.  T-lymphocyte number is reduced in patients with head and neck and oral cancers. Leukocyte function, lymphokine production and monocyte chemotaxis are also impaired , Changes in humoral immunity in patients with head and neck cancer are less profound and less well defined. 
Circulating immune complexes (CIC) are now viewed as regulators of both cellular and humoral immune responses by virtue of their capacities to interact with antigen receptor bearing lymphocytes and sub-population of T and B cells as well as with macrophages having FC and C receptors. 
Both exogenous and endogenous antigens can trigger pathogenic immune complexes, which are increasingly recognized as the cause of many disease in animals and humans, including neoplasia. ,, In some neoplasia, the quantity of CIC appears to be related to the tumor burden ,,,,,, while in other, CIC does not appear to be related to tumor burden or prognosis. , The reason for this difference may be due to the fact that some tumors are poorly immunogenic, while in some, antigens may be shed only intermittently. It is also known that not all immune complexes are damaging, since sensitive methods of detection showed low levels in people with no apparent disease. , Even though immune complexes have been demonstrated to have blocking activity on the cellular immune responses, the exact mechanism is not clear. 
Measurement of CIC in biological fluids has become increasingly important for diagnosis and assessment of prognosis in the management of patients of high risk group.
| > Materials and Methods|| |
The study was carried out on 90 individuals randomly selected from OPD and divided into three groups. Age group of these patients ranged from 20 to 55 years, with the mean age being 30.83 years.
Patient history and clinical findings were recorded in specially prepared proforma and were divided into three groups.
Group I: The control group consisting of 30 healthy individuals who gave no history nor presented with any signs of systemic disease or pathological oral lesions.
Group II: Consisting of 30 individuals with clinically and histopathologically confirmed diagnosis of oral potentially malignant lesions / conditions (oral submucous fibrosis, lichen planus and leukoplakia).
Group III: Consisting of 30 individuals with clinically and histopathologically confirmed carcinoma of oral cavity that were grouped according to the degree of differentiation.
Under aseptic condition, 5 c.c. of blood was drawn from all individuals. All patients in group III were treated with 60 Co. In patients with oral squamous cell carcinoma, blood was withdrawn before onset of radiotherapy, during radiotherapy (i.e. after 2400 rad) and after one week of completion of radiotherapy (i.e.after 4500-5000 rad). Serum was separated by centrifugation at 3000 rpm.
Polyethylene glycol (PEG) precipitation method used by Creighton et al in 1973  with slight modification was used for the present study. The serum was diluted 1:3 with borate buffered saline (BBS, 0.1 M boric acid, 0.025 M disodium tetraborate, 0.075 M sodium chloride pH 8.4). 0.22 ml of diluted sera was mixed with 2 ml of 4.16% of PEG (Mol. Wt. 6000) in BBS. The final serum dilution was 1:30 and final PEG concentration was 3.75%. The mixture was incubated at 4 o C overnight.
Each sample was matched with a control tube containing serum sample and BBS alone. The absorbance (optical density) was measured in a "Milton Roy Spectronic 1201 spectrophotometer" at 450 nm, to assess the turbidity formed due to the precipitation of immune complexes.
The increase in turbidity due to CIC insolubilization was calculated and expressed as PEG index.
PEG index = (OD 450 with PEG - OD450 with BBS) × 1000, where OD denotes optical density
The 't' test was used for testing the difference between mean values of two independent groups. The significance was determined from the table value of 5% i.e. P (0.05) and 1% i.e. P (0.01).
'Z' test was applied to calculate the significant difference between the mean of two samples when the size was large, i.e. n>30.
| > Results|| |
[Table 1] shows control group which consisted of 22 males and 8 females with age ranging between 20 and 55 years, with the mean age of 30.83 years. Group II consisted of 25 males and 5 females with premalignant lesions and conditions, with the mean age being 32.5 years as compared to Group III which consisted of 30 patients with oral squamous cell carcinoma of various sites of oral cavity, having mean age of 52.56 years. The mean age in precancerous and cancerous group was higher than the control group. The mean PEG index of all the patients in various groups is shown in [Table 2].
|Table 2: Maximum, minimum, mean CIC levels along with standard deviation and error in various groups|
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The mean CIC level in control group was 59.56 and in premalignant group the mean CIC level was 75.93. Z test was found to be highly significant (Z = 23.36, P < 0.001) as shown in [Table 3].
|Table 3: Comparison of mean CIC level in control, precancer and malignant group|
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The mean CIC value of premalignant group (75.93) was compared with the malignant group by applying 'Z' test and was found to be highly significant (Z = 18.68, P < 0.001)as shown in [Table 3].
It was observed that the mean CIC values had gradually increased from control to premalignant and further in malignant group [Table 3], [Figure 1]. Amongst the premalignant group, the highest mean CIC value was found in leukoplakia (83.42 ± 9.10) followed by lichen planus (78.57 ± 3.24) and then by oral submucous fibrosis (71.5 ± 14.96).
In premalignant group, there were 4 patients that showed no degree of dysplasia with the mean CIC level of 67. There were 25 patients with mild dysplasia whose mean CIC value was 77.16 and only one patient showed moderate degree of dysplasia with CIC value of 81 [Table 4].
In malignant group, mean CIC level was 92.66 [Table 3] as compared to control group (59.56), which was found to be highly significant (Z = 44.97).
There were 22 patients with well differentiated squamous cell carcinoma with the mean CIC level of 90.09, 7 patients of moderately differentiated (MD) squamous cell carcinoma with mean CIC level of 78.85, and 1 patient with poorly differentiated (PD) squamous cell carcinoma with CIC level of 128 [Table 5].
No correlation could be established between degree of differentiation and degree of dysplasia with the CIC levels in malignant and premalignant groups respectively [Table 4] and [Table 5].
Thirty randomly selected patients were monitored before radiotherapy, during radiotherapy (after 2400 rad) and after radiotherapy (after one week of 4500 - 5000 rad). The mean CIC value (± S.D.) before radiotherapy was 92.66 ± 13.96 compared with that of during radiotherapy 89.33 ± 23.48 and after radiotherapy 77.53 ± 11.63 [Table 6], [Figure 2].
'Z' test was applied to compare the difference in mean CIC level before radiotherapy with that of during radiotherapy (Z = 2.98, P < 0.01) and the CIC level during radiotherapy with that of post-radiotherapy (Z = 10.88, P < 0.01), the difference was found to be significant. When the mean value of before radiotherapy was compared to that of after radiotherapy, the difference was highly significant (Z = 16.37, P < 0.001) [Table 7].
There was a gradual decrease in CIC level following radiotherapy. There was not much decrease in CIC level when observed at 2400 rad, compared with the mean CIC level before radiotherapy. But after one week of 4500-5000 rad, there was significant decrease in the CIC level. It was also observed that there was increase in the CIC levels in five patients after radiotherapy (after 2400 rad).
| > Discussion|| |
The results show a significant increase in CIC levels in patients with premalignant lesions and OSCC when compared with controls [Figure 1]. This represents the host defense against tumor antigen by production of antibodies. It has been observed that tumor-associated antigens are constantly released into the circulation, where they evoke an immune response and finally combine with antibodies produced.  This together with the immune complexes formed as a result of non-specific oral infection by microorganisms could be a possible explanation for the increase in CIC. 
Prabha et al, in a study of 1995 patients showed a highly significant elevation of CIC (± S.E.) in cancer patients (76.4 ± 5.56) compared with (37.2 ± 2.69) in normal and (50.1 ± 5.62) in patients who chew betel leaf, areca nut and tobacco, which is comparable to the present study. However, they found that there was no significant difference in the CIC levels in oral cancer patients (mean CIC 76.4 ± 5.56, P < 0.001) and those with premalignant lesion (mean CIC 73.9 ± 5.07, P < 0.001).
In the present study of premalignant group, high levels of CIC were present in leukoplakia followed by lichen planus and then oral submucous fibrosis. Thus, the high value of mean CIC levels in leukoplakia and lichen planus may point to the risk of their malignant potential; hence, a radical treatment should be instituted in such conditions. The clinical relevance of the presences of CIC in premalignant patients is difficult to assess. The occurrence of CIC in premalignant patients and later conversion into malignancy could be an after effect of the inhibitory action of CIC on the anti-tumor immune response.  which has been observed on natural killer cell activity and tumor specific cell-mediated cytotoxicity. , These are the major lines of defense against tumor progression. This along with other factors like genetic susceptibility, viral and chemical promoters, etc. might be important factors in conversion of these lesions into frank malignancy in about 3-5% of these patients. 
Jane et al, in their study showed high levels of CIC in patients with submucous fibroses where as minimal levels were observed in oral lichen planus patients. Sallay et al, studied the CIC in patients with oral lichen planus and leukoplakia by PEG precipitation method and found CIC positivity higher in oral lichen planus group with diabetes, than in the individuals with oral lichen planus only, but could not find CIC positivity in control patients having diabetes.
Significantly high levels of CIC in malignant lesion of the oral cavity in the present study could be because of carcinogenic action which alters the cellular components causing production of probably low avidity antibodies forming CICs. 
In the present study, no correlation could be assessed between level of CIC in patient with OSCC and in premalignant lesion affecting oral cavity with degree of differentiation and degree of dysplasia respectively. This finding correlates with Abrahan et al,  Vlock et al and Balan et al. 
This indicate that CIC levels cannot be used alone to determine the severity of the disease. Even though more of tumor antigens are shed into the system as the severity of the diseases increases, only a part of it binds to the antibody to form CIC. It has been observed that there is a fall in the circulating antibody levels in the course of rapid growth due to absorption of tumor antigens by tumor cell membranes. 
The analysis of antigen and antibody components in the CIC from individual patients may be helpful in further understanding the etiology of these lesions.
Ristow et al,  showed no significant difference between levels of CIC in a patient with colon cancer, but a good correlation could be found by Abrahan et al,  Balan et al and Balaram et al. 
Balan et al, tried to correlate the mean value of CIC with the TNM staging of the oral cancer by PEG precipitation method. They found that the mean value of CIC between stage II group and stage III group was not significant. But the difference between stage III and stage IV groups was statistically significant. This could mean that up to stage III, the liberation of antigen into the circulation remains more or less constant. In stage IV there must be an outburst of antigen into circulation and precipitation into high titer values.
Radiotherapy is one of the main methods of treatment of cancer. It can not only decrease the tumor load but can also depress the immune function of the patients. A good correlation was observed in our study with patient undergoing radiotherapy, showing a definite fall in the level of CIC during, and after one week following radiotherapy, thus indicating that levels of CIC can be used to determine the prognosis of a disease. A high level would probably indicate a bad prognosis or a high incidence of recurrence or metastases as compared to low levels.
It was also observed that there was increase in the CIC levels in five patients after radiotherapy (after 2400 rad), which may be because of two reasons, first due to release of the antigen-antibody complexes from the cell surface into the system, and secondly due to formation of fresh immune complexes of other cellular components following the increased cellular breakdown, due to radiotherapy.
Thomas Abraham et al, did a serial monitoring of CIC levels in patients following radiotherapy for 30 months by PEG precipitation method. They found a sudden increase in the levels of CIC immediately following radiotherapy and this increased CIC level extended on an average over three weeks after which it showed a tendency to fall. They also noticed that the elevated level of CIC was maintained in patients with residual disease and in patients who had local recurrences. This increase, even though small, was evident prior to clinical detection of the recurrence. After 30 months following radiotherapy, the CIC levels in patients without any signs of disease were lower than the pre radiotherapy levels.
Rin et al, in their study showed that the CIC did not differ significantly before and after the combined surgical, radio surgical and radiation therapy, where as Lofty et al, showed a significant decrease in CIC level after surgical eradiation of neoplasm. This diagnostic parameter proved to be of great significance in monitoring therapy in patients with various types of malignancies. Sameena Praveen et al, showed a gradual fall in CIC which was statistically significant following post treatment phase. No correlation was found between CIC and stages of disease of squamous cell carcinoma of head and neck, nodal status, site of disease, recurrence or survival. 
Hu De-en et al, in their study of 123 patients with nasopharyngeal carcinoma observed that CIC levels six to eight months after radiotherapy showed marked decrease in comparison with two to three months after radiotherapy thus correlating with severity and thus determining the prognosis of the disease.
Very few studies have been carried out on the effect of CIC on patient exclusively undergoing radiotherapy for oral squamous cell carcinoma.
Further studies are required to observe the CIC level at various intervals after the completion of radiotherapy before coming to any firm conclusion.
| > Conclusion|| |
It can thus be concluded that the pretreatment levels of CIC can be used as a prognostic indicator. A high CIC level could probably indicate a poor prognosis. Thus, CIC can be helpful in early detection of a lesion, understanding the malignant potential of the premalignant lesion management, and monitoring the efficacy of treatment.
Although tumor antigen-antibody ICs seem to play important role in the immunopathy and course of the neoplastic disease, the way in which they act is not yet fully understood. A better understanding of immune complex constituents and its size may be required before a pathologic relationship of circulating immune complexes to cellular immune function in patients with cancer; premalignant lesions can be assigned on the basis of CIC analysis alone. Antigenic makeup of CIC in cancer patients reveals the host immune response to variety of overlapping antigenic stimuli and hence paves way for further studies.
A detailed long term post-radiotherapy study of the antigen and antibody components in the CIC may be helpful in understanding the pathophysiology of lesion and the immunity of the patients.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]