|Year : 2015 | Volume
| Issue : 1 | Page : 3-6
Quantitative analysis of C-reactive protein in potentially malignant disorders: A pilot study
Srilalitha Kaja, Sashi Kiran Sanapala Venkata Naga, Kattappagari Kiran Kumar, Neelima Dasari, Lalith Prakash Chandra Kantheti, Baddam Venkat Ramana Reddy
Department of Oral Pathology, SIBAR Institute of Dental Sciences, Guntur, Andhra Pradesh, India
|Date of Web Publication||20-May-2015|
Dr. Kattappagari Kiran Kumar
Department of Oral Pathology, SIBAR Institute of Dental Sciences, Guntur, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Background: Recent advances in understanding complex tumor interactions have led to the discovery of an association between inflammation and cancer. An abundance of pro - inflammatory cytokines in a tumor micro-environment can lead to angiogenesis, thus favoring neoplastic growth. Serum C reactive protein is a sensitive marker of inflammation and may have significant prognostic value as early biomarker for cancer diagnostics. Aims and Objectives: This was a pilot study done to assess the serum C reactive protein levels in potentially malignant disorders (PMDS) and to evaluate their role as prognostic marker. Materials and Methods: The study sample consisted of 20 cases of oral potentially malignant disorders (10 each of Leukoplakia, Oral Sub mucous fibrosis) confirmed by histopathological examination and 10 controls. All the samples were subjected to C - reactive protein analysis by immunoturbidometery. Results were subjected to Statistical analysis. Statistical analysis: Data was entered in data base management of the software SPSS version 20.0. Comparison of three groups with respect to C reactive protein levels was done by one way ANOVA. Pair wise comparison of three groups was done by Turkeys multiple post hoc procedure. Results: Mean C reactive protein levels in leukoplakia was 0.33±0.17, in oral submucous fibrosis was 0.58±0.83 where as in controls it was 0.26±0.05. In potentially malignant disorders, C reactive protein was slightly elevated when compared with the controls. Conclusion: Our findings demonstrate that serum C reactive protein concentration is associated with subsequent development of oral cancer and could serve as a potential prognostic biomarker.
Keywords: Potentially malignant disorders, C reactive protein, oral cancer
|How to cite this article:|
Kaja S, Naga SS, Kumar KK, Dasari N, Kantheti LC, Reddy BR. Quantitative analysis of C-reactive protein in potentially malignant disorders: A pilot study. J Orofac Sci 2015;7:3-6
|How to cite this URL:|
Kaja S, Naga SS, Kumar KK, Dasari N, Kantheti LC, Reddy BR. Quantitative analysis of C-reactive protein in potentially malignant disorders: A pilot study. J Orofac Sci [serial online] 2015 [cited 2021 Sep 28];7:3-6. Available from: https://www.jofs.in/text.asp?2015/7/1/3/157355
| Introduction|| |
The chewing of tobacco products and smoking are endemic to the south-east Asian countries. It leads to the occurrence of potentially malignant disorders (PMD) and oral squamous cell carcinoma (OSCC). OSCC ranks sixth among various types of cancer.  The risk of malignant transformation of patients with PMD increases day by day and hence it is very important to assess the prognosis of these patients at an early stage. If identified, the incidence of death rates due to OSCC can be reduced considerably.  The transformation of PMD into OSCC involves contribution of both external and internal factors.  There are not many studies on proteins and early biomarkers that could help clinicians select a suitable treatment strategy for patients with PMD and oral cancer.  One such biomarker that can be used is the C-reactive protein (CRP). It has been identified that CRP increases during both acute and chronic inflammatory conditions. As it is well-known fact that inflammation and cancer are linked, the role of this protein has to be identified in PMD and OSCC.  The synthesis of CRP in hepatocytes is regulated by some of the pro-inflammatory cytokines such as interleukin (IL-1) and 6 and tumor necrosis factor. Few studies indicate that these markers are elevated in some of the malignancies. It is gradually becoming more evident that in addition to tumor stage, the prognosis of cancer also depends on the complex processes of interaction between tumor and host's inflammatory reaction. 
There are two hypotheses to explain how CRP acts on the cell during inflammation. The first one is known as the induction hypothesis, where either the acute or chronic inflammation leads to increased CRP levels which in turn leads excessive cellular proliferation and also causes irreversible DNA damage.  The second hypothesis is mainly dependent on the immune response of the host and is known as the "response hypothesis." According to this hypothesis, the immune response of the host in cancer results in the increased levels of CRP.  However, it is still perplexing how CRP levels are elevated in beginning of cancer and if it can considered as one of the risk factors for carcinogenesis. 
There are few studies where they have found an association between elevated serum CRP levels and cancers of the colorectal region and lung. , On the other hand, there are studies that have revealed that CRP can be used as a prognostic marker.  In squamous cell carcinoma of esophagus, it has been established that increased CRP is an indicator of a poor prognosis.  There are very a small number of studies in the literature where an association between serum CRP and PMD and head and neck cancers. Therefore, the present study was conducted to estimate the serum CRP levels in PMD to infer their significance as a prognostic marker.
This was a pilot study done to assess the serum CRP levels in PMD and to evaluate their significant role as a prognostic marker.
| Materials and Methods|| |
Twenty patients with PMD were included in this study. All the subjects were patients attending the Outpatient Department of SIBAR Institute of Dental Sciences, Guntur, Andhra Pradesh. The 20 subjects with PMD consisted of ten cases of oral submucous fibrosis (OSMF) and 10 cases of leukoplakia. The criteria for diagnosis of OSMF were the presence of burning sensation while eating spicy food, presence of fibrous bands, and loss of elasticity of buccal mucosa/labial mucosa and inability to open the mouth.  The WHO criteria were used for diagnosis of leukoplakia which is a white patch or plaque that cannot be considered clinically or histopathologically as any other lesion. The clinical diagnosis was confirmed by biopsy. Each of the OSMF cases showed an atrophic epithelium, juxta epithelial hyalinization, dense bundles of collagen fibers, and variable chronic inflammatory cell infiltration. Leukoplakia was diagnosed histopathologically using dysplastic features as criteria.  The exclusion criteria included OSMF in association with any other systemic diseases and subjects with oral and or pharyngeal malignancy. Patients under the treatment for OSMF and leukoplakia were also not included in the study.
Ten subjects were selected as a control from Out Patients Department of SIBAR Institute of Dental Sciences, Guntur, Andhra Pradesh. The control subjects were those who did not have any oral lesions. Patient's consent was taken in all cases, and a comprehensive clinical history was taken by trained a dental surgeon in predetermined case sheet. The study was conducted after obtaining clearance from the Institutional Ethical Committee. 5 ml of blood samples collected was drawn from all the 30 patients and serum was separated. Serum CRP levels were estimated using immunoturbidimetry methods (Bio Majestry R JCA-BM), the normal reference range considered as 0.0-0.6 mg/dl. Two observers independently made estimation for all the samples. There was no statistically significant inter or intra-observer variation.
Data entry and analysis were performed using the software SPSS version 20.0 (IBM, Armonk, New York, USA). Descriptive statistics was used to determine the frequency, percentage, mean, median, SD, and range. Comparison of groups with one-way ANOVA, pairwise comparisons of three groups with respect to CRP values was done by Tukey's multiple post hoc procedure.
| Results|| |
The mean age of patients in the control group was 46.00 ± 17.20. The mean age of patients with leukoplakia was 58.20 ± 7.60 and with OSMF was 36.90 ± 12.95 [Figure 1]. 30.0% of the cases with leukoplakia were beedi smokers, whereas 70% of OSMF patients had habit of panparag chewing [Figure 2]. Mean CRP levels were highest in OSMF (0.58 ± 0.83), followed by leukoplakia (0.33 ± 0.17). The mean value of CRP among control subjects was 0.26 ± 0.05. Comparison of the three groups with respect to CRP levels by one-way ANOVA test did not show statistically significant results (≥0.05) [Table 1]. Pairwise comparison of three groups with respect to CRP value by Tukey's multiple post-hoc procedures was also not statistically significant (≥0.05) [Table 2].
|Figure 1: Comparison of mean age in oral submucous fibrosis, leukoplakia, and control subjects|
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|Figure 2: Comparison of habits with oral submucous fibrosis, leukoplakia, and control subjects|
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|Table 1: Mean CRP levels and comparison of three groups (control, leukoplakia, and OSF) with respect to CRP value by one-way ANOVA|
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|Table 2: Pairwise comparison of three groups (control, leukoplakia, and OSF) with respect to CRP value by Tukey's multiple post-hoc procedures|
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| Discussion|| |
The incidence of death rates due to cancer is increasing very rapidly for the past two decades in our country. The main reason is due to habits like tobacco consumption in the form of chewing or smoking. Numerous research scholars are making efforts to fight against this deadly disease.  There have been studies in the literature that show that there is the relation between chronic inflammation and oral cancer. Other than inflammation, there are several other causes such as human immune deficiency virus, viral hepatitis B, and human papilloma virus.  One of the important markers of inflammation is CRP. There are two hypotheses to explain how chronic inflammation is associated with CRP. First hypothesis states that due to the excessive increase in the number of chronic inflammatory cells, activation of a flow of cellular functions occurs leading to initiation of irreversible cell damage.  The second theory is that the immune response of the host as a consequence of tumor growth itself could be the reason for the elevation of CRP levels.  But still it is perplexing how CRP is important for the genetic onset of cancer or whether elevated CRP levels has some role in biology of cancer. 
C-reactive protein is a receptive marker of inflammation and cancer that is elevated in response to infection and tissue harm in the active phase of diseases.  In the acute phase reactions, the CRP levels are primarily increased in the liver and additional organs in response to stimulation by IL-6.  CRP can be increased by both acute and chronic stimulation. It also plays a very important role in immunity by acting as a defense against bacterial and viral infections.  Elevation of CRP has also been observed in connective tissue diseases, cardiovascular diseases, infections, inflammatory conditions, tuberculosis, rheumatoid arthritis, and women using oral contraceptives. 
Some of the research papers have observed an association between serum CRP levels and different types of malignancies such as esophageal, colorectal, renal, and prostate cancers.  In our study, majority of the panparag chewers had OSMF. This observation similar to the ones seen by Tilakaratne et al., in 2006,  whereas majority of the beedi smokers had the leukoplakia which is similar to study by Saraswathi et al.  Kumar and Bhateja  studied CRP levels in oral precancer and cancer in which they observed that it was elevated in PMD similar to our study where we observed that CRP levels were highest in OSMF followed by leukoplakia. There are many studies which show that CRP levels increase with cancer, but there are few studies where they have documented elevated of CRP levels in PMD.
Many studies in the past have shown that CRP levels increase as cancer progresses. In our study, we have assessed the levels of CRP in PMD such as leukoplakia and OSMF. The levels of CRP were not significant when compared with all the three groups but when compared between OSMF and leukoplakia, OSMF patients showed prominent elevation of CRP which could be because of risk of high malignant transformation of OSMF. The results obtained in our study could also be due to the small sample size.
| Conclusion|| |
Chronic inflammation plays an important role in cancer initiation, progression, and metastasis. CRP is a nonspecific marker of systemic diseases and inflammation and is not recommended for prediction of cancer incidence and progression of PMD. However, CRP can contribute toward the management of these diseases. We need to do further studies with large sample to assess regarding CRP levels and PMD.
| References|| |
NCDS and Oral Cancer Rationale for Inclusion in Sear and Action Plan and Voluntary Targets Technical Working Group Meeting on Regional Action Plan and Targets for Prevention and Control of Non communicable Diseases Bangkok, Thailand; 11-13 June, 2013.
Raval GN, Patel DD, Parekh LJ, Patel JB, Shah MH, Patel PS. Evaluation of serum sialic acid, sialyltransferase and sialoproteins in oral cavity cancer. Oral Dis 2003;9:119-28.
Liao CT, Wang HM, Ng SH. Good tumor control and survivals of squamous cell carcinoma of buccal mucosa treated with radial surgery with or without neck dissection in Taiwan. Oral Oncol 2006;42:800-9.
Pepys MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol 1983;34:141-212.
Siemes C, Visser LE, Coebergh JW, Splinter TA, Witteman JC, Uitterlinden AG, et al.
C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: The Rotterdam Study. J Clin Oncol 2006;24:5216-22.
Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420:860-7.
Baron JA. Epidemiology of non-steroid inflammatory drugs and cancer. Prog Exp Tumor Res 2003;37:1-24.
Erlinger TP, Muntner P, Helzlsouer KJ. WBC count and the risk of cancer mortality in a national sample of U.S. adults: Results from the Second National Health and Nutrition Examination Survey mortality study. Cancer Epidemiol Biomarkers Prev 2004;13:1052-6.
Zhang SM, Buring JE, Lee IM, Cook NR, Ridker PM. C-reactive protein levels are not associated with increased risk for colorectal cancer in women. Ann Intern Med 2005;142:425-32.
Gockel I, Dirksen K, Messow CM, Junginger T. Significance of preoperative C-reactive protein as a parameter of the perioperative course and long-term prognosis in squamous cell carcinoma and adenocarcinoma of the oesophagus. World J Gastroenterol 2006;12:3746-50.
Neville BW, Damm DD, Allen CM, Bouquot JE, editors. Oral and Maxillofacial Pathology. 2 nd
ed. USA: W.B. Saunders Publication; 2002. p. 349-50.
Baxi BR, Patel PS. A report on clinical importance of serum glycoconjugates in oral cancer. Indian J Biochem 1990;5:139-44.
Allin KH, Bojesen SE, Nordestgaard BG. Base line protein is associated with incident cancer and survival in patients with cancer. J Clin Oncol 2009;27:2217-24.
Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ. C-reactive protein and the risk of incident colorectal cancer. JAMA 2004;291:585-90.
Lehrer S, Diamond EJ, Mamkine B, Droller MJ, Stone NN, Stock RG. C-reactive protein is significantly associated with prostate-specific antigen and metastatic disease in prostate cancer. BJU Int 2005;95:961-2.
Ablij H, Meinders A. C-reactive protein: History and revival. Eur J Intern Med 2002;13:412.
Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: Review on aetiology and pathogenesis. Oral Oncol 2006;42:561-8.
Saraswathi TR, Ranganathan K, Shanmugam S, Sowmya R, Narasimhan PD, Gunaseelan R. Prevalence of oral lesions in relation to habits: Cross-sectional study in South India. Indian J Dent Res 2006;17:121-5.
Anand Kumar C, Bhateja S. Altered C-reactive protein levels in serum of oral pre cancer patients in comparison with healthy control. Int J Oral Maxillofac Pathol 2011;2:16-9.
[Figure 1], [Figure 2]
[Table 1], [Table 2]