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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 13  |  Issue : 3  |  Page : 164-168

C-reactive protein levels: A prognostic marker for patients with head-and-neck cancer


1 Department of Oral and Maxillofacial Surgery, School of Dental Sciences, Krishna Institute of Medical Sciences, Deemed University, Karad, Maharashtra, India
2 Department of Oral and Maxillofacial Surgery, Sri Venkateshwara Dental College and Hospital, Bannerughatta, Anekal Road, Bengaluru, Karnataka, India
3 Department of Oral Medicine and Radiology, Sathyabama Dental College and Hospital, Chennai, India
4 Department of Oral Pathology and Microbiology, Sarjug Dental College and Hospital, Darbhanga, Bihar, India
5 Department of Pedodontics and Preventive Dentistry, Hi-Tech Dental college and Hospital, Mullana, Ambala, India
6 Department of Periodontics and Implantology, MMCDSR, Deemed to be University, Mullana, Ambala, India
7 Consultant Dental Surgeon and Oral Pathologist, New Delhi, India

Date of Submission17-Aug-2020
Date of Acceptance29-Nov-2020
Date of Web Publication11-Jul-2021

Correspondence Address:
Parkhi Gupta
Consultant Dental Surgeon and Oral Pathologist, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJDS.IJDS_137_20

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  Abstract 


Background: C-reactive protein (CRP) is a nonglycosylated pentameric polypeptide comprising 206 amino acid residues. CRP causes activation of the classical complement pathway by binding to various autologous and extrinsic ligands exposed on membranes of injured, necrotic, or cells undergoing apoptosis. There is evolving evidence which strongly suggests that CRP is an inflammatory marker and is significantly elevated in patients diagnosed with tumors such as hepatocellular, pulmonary, and breast carcinomas. In addition, serum CRP level has been shown to be associated with size of tumor (T), clinic-pathological characteristics, and metastasis to lymph nodes. Aim: The aim of this study was to compare serum CRP levels in potentially malignant disorders and oral malignancies. Materials and Methods: This cross-sectional prospective study was designed to study serum CRP levels in patients with oral potentially malignant disorders (leukoplakia and oral submucous fibrosis), patients with oral squamous cell carcinoma, and normal controls. Study participants were divided into four groups: (1) Group I comprising 40 patients with leukoplakia, (2) Group II comprising 40 patients with oral submucous fibrosis, (3) Group III comprising 40 patients with oral squamous cell carcinoma, and (4) Group IV comprising 40 controls. Five milliliters of venous blood was collected after venipuncture from the antecubital vein followed by centrifugation, and serum was separated. This separated serum was analyzed for CRP levels using SPINREACT kit and semi-automated biochemical analyzer (Kyoto, Japan). All obtained data were entered into Microsoft Excel Worksheet 2007, and tabulations were performed using SPSS 16 (Statistical Package for the Social Sciences) software (IBM Corporation, Chicago, IL, USA). P < 0.05 was considered statistically significant. Results: Mean ± standard deviation values derived were 5.5 ± 4.8 mg/dl (Group I), 6.1 ± 4.9 mg/dl (Group II), 10.5 ± 2.4 mg/dl (Group III), and 2.1 ± 1.6 mg/dl (Group IV), respectively. On applying one-way analysis of variance for comparison of three groups, P < 0.003 was obtained. The results implied that an extremely significant statistical correlation existed between all studied groups when serum CRP levels were compared. Conclusion: Serum CRP levels are prognostic markers in oral potentially malignant disorders and oral malignancies.

Keywords: C-reactive protein, malignancies, potentially malignant disorders, serum


How to cite this article:
Mouneshkumar C D, Deepa, Gulati S, Jha A, Khangembam M, Gupta S, Gupta P. C-reactive protein levels: A prognostic marker for patients with head-and-neck cancer. Indian J Dent Sci 2021;13:164-8

How to cite this URL:
Mouneshkumar C D, Deepa, Gulati S, Jha A, Khangembam M, Gupta S, Gupta P. C-reactive protein levels: A prognostic marker for patients with head-and-neck cancer. Indian J Dent Sci [serial online] 2021 [cited 2021 Sep 20];13:164-8. Available from: http://www.ijds.in/text.asp?2021/13/3/164/321170




  Introduction Top


C-reactive protein (CRP), an alpha-globulin, is a member of the family of pentraxin proteins. It has a molecular weight measuring between 11,000 and 140,000 Daltons. It was first discovered by Tilet and Francis in 1930 from plasma samples of pneumonia patients. It was named as “CRP” due to the ability to cause precipitation of C-polysaccharide component of Streptococcus pneumoniae. It is mainly synthesized in the liver, and its serum or plasma levels measure lesser than 0.3 mg/dl. Its synthesis is under hepatocytic regulation of interleukin-1, interleukin-16, and tumor necrosis factor-alpha (TNF-α) which are pro-inflammatory cytokines.[1] These proteins along with other acute-phase reactant proteins are usually present at a very low concentration within plasma, however, their levels may rise significantly within a span of 72 h following injury to tissues or following any infection. Advantages of analyzing CRPs is that their levels begin to rise after disease onset while an increase in level is reported following four to 6 h following an acute injury to tissues while serum levels of other acute-phase reactant proteins show an increase 24–48 h following any tissue injury.[2] CRPs are constantly traced during bacterial and viral infections, malignant conditions, tuberculosis, and acute rheumatic fever and in individuals undergoing transfusion of blood and surgeries. This protein acts by prevention of neutrophilic adhesions to endothelium by downregulating the L-selectin expression and inhibition of neutrophilic superoxide generation. This stimulates interleukin-6 receptor antagonist synthesis by mononucleated cells. It also stimulates the production of tissue factor by peripheral blood monocytes among humans and exerts a procoagulant mechanistic effect.[3]

The acute-phase proteins have been defined as “those proteins wherein alterations of concentration change by approximately 25%.” These proteins are mainly comprised of fibrinogen, serum amyloid A, and CRP.[4]

CRP is a type I acute-phase protein that shows a thousandfold increase in inflammatory and malignant conditions. This protein has opsonizing capabilities, thereby activating the complement system. Its level shows a spike in cardiovascular and connective tissue diseases, various infectious conditions, periodontal diseases, and various types of malignancies.[1] Acute-phase protein release response is a highly nonspecific process that takes place as an initial response toward infections, necrosis occurring due to ischemia, injury, or any of the malignant lesional conditions. The CRP additionally causes bacterial opsonization for binding of complements and activating the complement system.[5]

There are mainly two types of hypothesis which explain the rise in CRP levels. The first hypothesis is known as the '”induction hypothesis.” It was proposed by Rudolf Virchow. According to this hypothesis, chronic inflammation causes increased cellular proliferation and an increase in irreversible type of damage to DNA. Persistence of chronic inflammatory response coupled with inflammation causes growth of tumor, metastatic disease spread, and progression alongside immunosuppressive activity.[3] Furthermore, according to this hypothesis, cancer originates at chronic inflammatory site and is associated with cancer risk. For example, human papillomavirus, hepatitis B virus, and human immunodeficiency virus infections show elevated CRP levels and modified immunological responses. This hypothesis can be substantiated by the fact that the risk of colorectal carcinoma development reduces with chronic usage of nonsteroidal anti-inflammatory agents such as aspirin.[6]

The second hypothesis is known as the “response hypothesis.” According to this hypothesis, the host immune response is a consequence of timorous growth. Leukoplakia is the most common premalignant lesion reported within the oral cavity, while the malignant transformation of oral submucous fibrosis falls within a range varying from 7% to 13%.[7] CRP has a pentameric proteinaceous structure. On mild inflammatory conditions and viral infections, its level rises to 10–50 mg/dl. Higher concentrations ranging between 50 and 200 mg/dl can be obtained in active infections and acute inflammatory conditions. The baseline CRP levels undergo wide variations even on a daily basis. Major factors influencing CRP levels are obesity, smoking, or any other metabolic or inflammatory disease.[8],[9]

CRP acts as a surrogate molecule for activity of interleukin-6. Its levels are nonspecific yet have proven a sensitive marker related to acute inflammation.[10] It also acts as a marker for inflammatory processes and cancerous conditions going within the human body.[11]

The serum CRP levels are also influenced by body mass index of a person. This has been shown by Gunter et al. where the positive association between body mass index and colorectal carcinoma was stronger in obese persons when compared to thin individuals. This can be related to adiposity-associated etiologic factors such as hyperinsulinemia. These investigators also supported the view that chronic inflammatory process existing within the colorectum is a considerable risk associated with carcinoma development.[12]

The aim of this study was to compare serum CRP levels in oral potentially malignant disorders and oral squamous cell carcinoma.


  Materials and Methods Top


This was a cross-sectional prospective study which was designed to include patients with oral potentially malignant disorders (namely, leukoplakia and oral submucous fibrosis), patients with histopathologically diagnosed oral squamous cell carcinoma, and normal controls. Study participants were divided into four groups:

  1. Group I: This group comprised 40 patients with clinically diagnosed leukoplakia
  2. Group II: This group comprised 40 patients with clinically diagnosed oral submucous fibrosis
  3. Group III: This group comprised 40 patients with histopathologically confirmed oral squamous cell carcinoma
  4. Group IV: This group comprised 40 normal controls.


Informed consent was obtained from all study participants after explaining them the study objectives. Exclusion criteria of the study were (1) absence of cardiovascular disease, (2) no connective tissue disorders such as rheumatoid arthritis and Sjogren's syndrome, and (3) patient not on any medications such as hyperlipidemic drugs and antihypertensive medications.

Inclusion criteria of the study were (1) histopathologically confirmed oral squamous cell carcinoma, (2) clinically confirmed leukoplakia and oral submucous fibrosis, and (3) no alcohol intake.

Five milliliters of venous blood was collected after venipuncture from the antecubital vein. This was followed by centrifugation and serum separation. The separated serum was immediately analyzed for CRP levels using SPINREACT kit and semi-automated biochemical analyzer (Kyoto, Japan). All obtained data were entered into Microsoft Excel Worksheet 2007, and tabulations were performed using SPSS 16 (Statistical Package for the Social Sciences) software (IBM Corporation, Chicago, IL, USA). P < 0.05 was considered to be statistically significant.


  Results Top


Mean ± standard deviation (SD) values obtained were 5.5 ± 4.8 mg/dl for Group I, 6.1 ± 4.9 mg/dl for Group II, 10.5 ± 2.4 mg/dl for Group III, and 2.1 ± 1.6 mg/dl for Group IV, respectively.[Graph 1]



On applying the statistical tool, one-way analysis of variance for comparing three groups' mean ± SD values, P < 0.003 was obtained [Table 1]. This implied that an extremely significant statistical correlation existed between all studied groups when serum CRPs were compared.
Table 1: Table demonstrating mean values of serum C-reactive proteins in studied groups and P value obtained

Click here to view



  Discussion Top


CRP is a highly conserved homopentameric protein, also known as “native CRP.” It undergoes irreversible dissociation at inflammatory sites. The native CRP is constituted of a discoid-shaped configuration comprising five noncovalently bound subunits arranged around a central pore.[13] This particular configuration is organized in a twin-layered β-sheet structure or a lectin fold. After undergoing dissociation, the free monomeric subunits are termed as “modified or monomeric CRP.” It is synthesized primarily in hepatocytes, but other cells such as macrophages, smooth muscle cells, lymphocytes, endothelial cells, and adipocytes are also considered as sites of CRP synthesis.[14] This molecule is synthesized in monomeric form and then is assembled into pentameric structure within endoplasmic reticulum. The CRP undergoes binding to damaged cell membrane. This leads to binding with terminal complexes of complements such as atherosclerosis.[2],[15] Elevated serum CRP levels have been shown to be associated with various types of malignancies such as non-small cell lung carcinoma, hepatocellular carcinoma, renal carcinoma, and prostatic carcinoma.[16]

India has consistently reported a high incidence of oral potentially malignant disorders and oral cancer when compared with the rest of the world. Also, seen is a very low 5-year survival rate. Gosavi and Torkadi compared that the serum CRP levels of 150 study participants which were divided into (a) 50 cases each of oral submucous fibrosis and oral squamous cell carcinoma and normal controls were 5.40 ± 4.79 mg/dl; 12.17 ± 11.38 mg/dl, and 2.20 ± 1.74 mg/dl, respectively.[17]

Gupta et al. in their study conducted in thirty individuals noted that 73.68% of patients diagnosed with poorly differentiated oral squamous cell carcinoma demonstrated high serum CRP binds when compared with well- and moderately differentiated oral squamous cell carcinoma (26.31%).[18] Vankadara et al. in their study found that the concentration of CRP was extremely high and statistically significant in squamous cell carcinoma when compared to oral potentially malignant disorder (P < 0.001).[4]

Similarly, Metgud and Bajaj reported high levels of CRP in oral potentially malignant disorders and oral squamous cell carcinoma cases.[19] Simeni et al. in a cross-sectional analysis conducted on 275 individuals observed that increased levels of CRP have no significant association with metastatic potential (P = 0.074), tumor size (T) (P = 0.09), nodal status (N) (P = 0.111), histopathological grade (P = 0.115), and type of malignancy (P = 0.124). They surmised that raised serum levels of CRPs have no prognostic value as a marker for tumor spread.[20]

Shrotiya et al. in their study investigating a relationship between CRP and prognosis of solid tumors demonstrated that significantly shorter rates of survival were associated with CRP levels when they were >5 mg/dl.[21]

Bhattacharjee et al. investigated serum CRP levels in oral potentially malignant disorders in 40 individuals from samples collected preoperatively. They reported an increase in the levels of CRPs in both leukoplakia and oral submucous fibrosis patients. Extremely significant P values were obtained on comparing sera levels of leukoplakia patients with oral submucous fibrosis (P = 0.0002).[3] Various other investigators such as Kumar and Bhateja[7] and Kaja et al.[8] have demonstrated that oral potentially malignant disorders have an association with elevated levels of CRPs. In a study by Kaja et al., oral submucous fibrosis patients demonstrated much elevated CRP levels in oral submucous fibrosis patients compared to those diagnosed with leukoplakia.[8]

Zeng reported in 79 individuals that the pretreatment serum CRP levels are associated with poor prognosis in nasopharyngeal carcinoma.[22]

Oliviera et al. reported higher TNF-α along with CRP in inflammation-associated processes. A positive correlation was reported between CRP levels and cancer-associated pain.[13] Furthermore, few studies have reported poor outcome when correlating high levels of CRPs with squamous cell carcinoma.[12],[13]

There are various prognostic indicators based on inflammatory mediators which have shown a good association with solid malignancies.[23] Song et al. have shown that raised levels of serum CRP have been linked with significant predictable parameter for evaluating a 5-year survival rate of Stage I esophageal carcinoma.[24]

Kruse et al. analyzed preoperative levels of CRP in 278 patients diagnosed with oral cancer and demonstrated that there was no significant correlation between metastasis (P = 0.468) and recurrence (P = 0.137).[6]

CRP upregulation is associated with tumor progression and poor prognosis in malignant tumors, for example, osteosarcoma, small cell lung carcinoma, and prostatic carcinoma. Kong et al. enrolled 72 study participants who had a history of recurrent gastric carcinoma. On analyzing their sera samples, high levels of CRPs were found to be significantly associated (P = 0.004) with greater size of the tumor (T) along with metastasis to regional lymph nodes (P = 0.003).[25]

Kruse et al. studied CRP levels from preoperative samples obtained from 278 oral cancer patients. This study did not find any significant correlation between raised levels of CRP and nodal metastasis (P = 0.465) and also recurrence (P = 0.137).[6] Kumar and Bhateja also reported higher mean CRP levels in severe grade of epithelial dysplasia indicating tendency for malignant transformation.[7]


  Conclusion Top


Inflammatory responses play a huge diversity of roles in different stages of development of tumor which include initiation, promotion, and transformation into malignancy which may undergo stromal invasion and regional and distant metastasis. Tumor formation and development are biological characteristics of all tumorous growths and also underlie various elements of inflammation in tumorous microenvironment. A variety of inflammation-related factors such as interleukin-6, interleukin-1β, and TNF-α have been found to be involved in a variety of signaling pathways which potentiate the progression of malignancies.

CRP is released within the body as a response toward inflammatory processes. Malignancies including oral cancer exhibit a strong association with chronic inflammation as well as oral cancer. It acts as a biomarker which reflects varying degrees of inflammatory process. Furthermore, various literature evidences have suggested a close association between CRP and various types of cancer. This study also demonstrates a significant correlation between oral potentially malignant disorders studied and oral squamous cell carcinoma due to the underlying inflammatory pathogenetic mechanism in these lesions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Sachin Jain, Vidhi Gautam, Sania Naseem. Acute-phase proteins: As diagnostic tool. J Pharm Bioallied Sci. 2011 ; 3(1): 118–27.  Back to cited text no. 1
    
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Sproston NR, Ashworth JJ. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front Immunol. 2018;9:1-11.  Back to cited text no. 2
    
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Bhattacharjee K, Girish HK, Mulgod S, Varsha VK, Nishathil L, Sunder VS. Comparison of serum C Reactive protein in oral potentially malignant disorders and in healthy individual. Res J Pharm Biol Chem Sci 2016;7:1285-91.  Back to cited text no. 3
    
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Vankadara S, Padmaja K, Balmuri PR, Naresh G, Reddy VG. Evaluation of serum C-reactive protein levels in oral premalignancies and malignancies: A comparative study. J Dent (Tehran) 2018;15:358-65.  Back to cited text no. 4
    
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Gani DK, Lakshmi D, Krishnan R, Emmadi P. Evaluation of C-reactive protein and interleukin-6 in the peripheral blood of patients with chronic periodontitis. J Ind Soc Periodontal 2009;13:69-75.  Back to cited text no. 5
    
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Kumar CA, Bhateja S. Altered C reactive protein levels in serum of oral precancer patients in comparison with healthy control. Int J Oral Maxillofac Pathol 2011;2:16-9.  Back to cited text no. 7
    
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Kaja S, Venkata Naga SK, Kumar KR, Dasau N, Kanthetic LP, Ramana Reddy BV. Quantitative analysis of C Reactive protein in potentially malignant disorders: A pilot study. J Orofac Sci 2015;7:36-40.  Back to cited text no. 8
    
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