The levels of squamous cell carcinoma antigen (SCC-Ag) and C-reactive protein (CRP) can be used to predict tumor invasion, lymph node metastasis, staging and survival in patients with oral cavity cancer. The present study analyzed the relationship between pre-treatment levels of SCC-Ag and CRP in relation to clinicopathological factors in patients with pharyngolaryngeal cancer (PLC) and determined whether elevated levels of CRP and SCC-Ag were associated with tumor metabolic activity via [18F] fluorodeoxyglucose positron emission tomography (FDG-PET). We retrospectively recruited one hundred and six PLC patients between June 2008 and December 2011. All patients received computed tomography (CT)/magnetic resonance imaging (MRI) and FDG-PET staging analyses, and the serum levels of SCC-Ag and CRP in these patients were measured prior to treatment. A SCC-Ag level ≥2.0 ng/ml and a CRP level ≥5.0 mg/L were significantly associated with clinical stage (P<0.001), clinical tumor status (P<0.001), and clinical nodal status (P<0.001). The elevation of both SCC-Ag and CRP levels was correlated with the standardized uptake value (SUV) max of the tumor (≥8.6 mg/L) and lymph nodes (≥5.7 ng/ml) (P = 0.019). The present study demonstrated that the presence of high levels of both pre-treatment SCC-Ag and CRP acts as a predictor of clinical stage, clinical tumor status, and clinical nodal status in patients with PLC. Moreover, elevated levels of SCC-Ag and CRP were associated with a high metabolic rate as well as the proliferative activity measured according to the SUVmax of the tumor and lymph nodes. Therefore, elevated levels of these two factors have the potential to serve as biomarkers for the prediction of tumor aggressiveness in cases of PLC.
Citation: Chen H-H, Wang H-M, Fan K-H, Lin C-Y, Yen T-C, Liao C-T, et al. (2013) Pre-Treatment Levels of C-Reactive Protein and Squamous Cell Carcinoma Antigen for Predicting the Aggressiveness of Pharyngolaryngeal Carcinoma. PLoS ONE 8(1): e55327. https://doi.org/10.1371/journal.pone.0055327
Editor: Jian-Xin Gao, Shanghai Jiao Tong University School of Medicine, China
Received: September 11, 2012; Accepted: December 21, 2012; Published: January 31, 2013
Copyright: © 2013 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no support or funding to report.
Competing interests: The authors have declared that no competing interests exist.
Head and neck cancer is the fourth most common cancer and leading cause of cancer-related deaths in Taiwan.  Amongst them, pharyngolaryngeal carcinoma (PLC) and oral cancer are prevalent and are associated with adverse lifestyles, including habitual tobacco, areca-quid (AQ) and alcohol use as well as human papilloma virus (HPV) infection. , .
Knowledge of prognostic factors would be beneficial when evaluating and counseling patients with these cancers. Notably, HPV infection status has been strongly associated with the therapeutic response and survival of oropharyngeal cancer patients; however, it was not shown to be related to tumor stage or clinicopathological factors.  Preoperative squamous cell carcinoma antigen (SCC-Ag) level is a marker for pathologic lymph node metastasis, advanced tumor stage, and an increased rate of distant metastasis in patients with oral squamous cell carcinoma (OSCC).  Elevated serum CRP, a sensitive marker of inflammation and tissue damage, has been correlated with shorter survival in cancer patients , , ,  Importantly, the combined use of these two factors is useful in the stratification of OSCC patients receiving radical surgery.  However, their significance in patients with pharyngeal and laryngeal cancers has not been carefully addressed.
Fluorodeoxyglucose positron emission tomography (FDG-PET) is a well-established tool for evaluating head and neck cancer.  The maximum standardized uptake valve (SUVmax) serves as a semi-quantitative simplified measurement of the tissue deoxyglucose metabolic rate and has been correlated with tumor proliferation rate, tumor grade and the expression of glucose transporters.  A high FDG uptake value is generally associated with a less favorable outcome. , ,  For example, FDG uptake in breast cancer is correlated with markers of biological aggressiveness that can normally only be evaluated in vitro postoperatively, including mitotic count and the Ki-67 labeling index.  Accordingly, hypermetabolic breast tumors typically receive a poorer prognosis than those that are hypometabolic, demonstrating the relevance of FDG-PET/computed tomography (CT) analyses to tumor biology. .
In this study, we investigated the significance of SCC-Ag and CRP levels in PLC patients and their relationship with various clinicopathological factors as well as 18F-FDG uptake levels on PET scans.
Patients and Methods
Patients with Pharyngolaryngeal Cancer
We retrospectively reviewed the charts of all patients newly diagnosed with PLC at our institute between June 2008 and Aug 2011. Patients with distant metastases at diagnosis or who were lost to follow up following diagnosis were excluded. Follow-up commenced at the time of cancer diagnosis and, for this study, completed at the earlier of either December 2011 or death. All patients were evaluated preoperatively with history, examination, routine bloods, chest radiograph, liver ultrasound, FDG-PET and either CT or magnetic resonance imaging (MRI) of the head and neck. .
Treatment of PLC
All patients were staged as per American Joint Committee on Cancer guidelines (AJCC, 2010 edition; ) and treated according to their clinicopathological features. As previously described, chemotherapy was administered on an outpatient basis in 14-day cycles and comprised 50 mg/m2 cisplatin (P) on Day 1 followed by 800 mg/m2 oral tegafur (T) per day and 60 mg oral leucovorin (L) per day for 14 days (PTL regimen).  In the chemotherapy/radiotherapy group, chemotherapy was terminated after three cycles if there was little-or-no tumor response. In responders, PTL regimens were continued for up to six cycles before radiotherapy. Patients with good partial responses at the primary site after neoadjuvant chemotherapy received radiotherapy or CCRT for organ preservation.
Radical surgery involved wide excision of primary tumors with at least 1 cm peripheral and deep surgical margins. Patients with advanced tumor stage (T3 or T4), lymph node extra-capsular spread (ECS), tumor depth ≥10 mm or poor tumor differentiation received postoperative radiotherapy or CCRT 4–8 weeks after surgery. , .
Radiotherapy involved a three-field technique and consisted of conventional bilateral opposing fields with a matching anterior lower neck portal. Daily fractionation size was 1.8 or 2 Gy and five fractions were delivered per week. The planning target volume was created by adding a 5 to 7 mm margin to the clinical target volume. For the group receiving radical surgery first, the post-operative radiotherapy dose was 60–68.4 Gy, depending on the pathology risk factor; for the organ preservation group, the dose range was 68.4–76 Gy.
Measurement of CRP and SCC-Ag Levels
Pre-treatment serum levels of CRP and SCC-Ag were measured in a fresh blood sample obtained at the time of diagnosis, prior to any form of medical intervention, to minimize inter-individual differences. Serum CRP levels were detected with a high-sensitivity assay (Sekisui Medical Co., Tokyo, Japan) using an auto-analyzer (Hitachi 7600-210; Hitachi Medico, Tokyo, Japan). Serum SCC-Ag level was measured using a commercially available chemiluminescent microparticle immunoassay (Abbott Japan Co., Ltd., Tokyo, Japan). Serum CRP cutoff was set at 5.0 mg/L as this level is internationally agreed to indicate inflammation.  The reference cutoff for serum SCC-Ag level was 2.0 ng/mL as previously published. , .
FDG PET (PET/CT) Imaging Protocol
FDG-PET/CT was used for the initial tumor survey. Patients fasted for 6 hours before scans and were then subjected to 370 to 444 MBq (10 to 12 mCi), with 18F-FDG administered intravenously. An oral contrast agent was administered during uptake time. Next, PET/CT scans (Discovery ST; GE Healthcare) combining a 16-slice spiral CT scanner were performed. The patients were scanned from head to mid-thigh; lower limbs were scanned if indicated. A positive finding was defined as a focus of increased 18F-FDG uptake with intensity higher than that of the surrounding tissues, which was localized according to hybrid images in an area that did not correspond to the physiologic bio-distribution of the radiotracer. Regions of interest (ROIs) were measured for lesions visible on PET images, as well as on simultaneously displayed axial, coronal, and sagittal tomograms.  The standardized uptake value (SUV), a semi-quantitative measure of radiotracer uptake, was calculated according to the following formula: SUV = tissue radioactivity concentration [nCi/mL]/[injected dose (mCi)/patient weight (g)].  SUVmax was defined as the highest activity concentration per injected dose per body weight (kg) after correcting for radioactive decay. The SUVmax of the primary tumor (SUVtumor-max) was calculated as the maximum pixel SUV within a ROI encompassing the tumor. The SUVmax of the lymph nodes (SUVnodal-max) was calculated in suspected regions of the neck. The reference cutoff value of the SUVtumor-max was 8.6 and of the SUVnodal-max was 5.7. .
Patients were followed monthly during the first 6 months after treatment, every 2 months for the following 6 months, every 3 months during the second year, and every 6 months thereafter. The patients were subjected postoperatively to hemograms, blood chemistry measurements, chest x-rays, and CT or MRI analyses at the 3rd, 6th and 12th month for the first year and then annually for the following 4 years. Patients who presented with abnormal clinical symptoms/signs or laboratory data underwent a bone scan and liver ultrasound for further evaluation.
The study was approved by the Institutional Review Board of Chang Gung Memorial Hospital, Linkou (IRB). The data (CRP and SCC-Ag) were analyzed in retrospective manner. The information was recorded by the investigator in a manner that subjects could not be identified directly or through identifiers linked to the subjects. No informed consent was requested by the IRB.
The following major variables were examined: CRP levels, SCC-Ag levels, SUV max of the primary tumor and neck lymph nodes, and clinical and pathological lymph node status. The statistical methods used included a univariate analysis with the chi-squared test, and a univariate analysis of survival differences was performed using the log-rank test. A two-sided P value <0.05 was considered statistically significant. These analyses were performed using the Statistical Package for the Social Sciences (SPSS) statistical software, version 19.0 (SPSS, Inc., Chicago, IL, USA).
Between June 2008 and August 2011, 106 consecutive patients (103 males; 3 females; mean age 54.3 years, range: 38–96 years) were newly diagnosed with PLC at our institute. The sites of their primary tumors, their clinical staging and the treatments they received are detailed in Table 1. Three patients were excluded from survival analyses as they were lost to follow-up after receiving palliative treatment. Median follow-up period was 14.1 months (range, 0.8–40.8 months). Forty-four patients (41.5%) were disease-free during the follow-up period, 25 patients experienced recurrent disease (23.6%), 17 patients had a partial remission (16%), and 20 patients were stable. Sixteen patients died of their disease during follow-up. The mean serum CRP level prior to treatment was 16.93 mg/L (± standard deviation (SD) 31.68), whereas the mean SCC-Ag level prior to treatment was 2.65 ng/mL (± SD 3.07). All patients also underwent FDG-PET prior to treatment; the mean SUVtumor-max was 13.05 (± SD 6.31), and the mean SUVnodal-max was 8.75 (±SD 6.20).
Relationship between CRP level, SCC-Ag level, SUVtumor-max and SUVnodal-max According to Clinicopathological Variables
The cutoff point for measurements of serum CRP level was set at 5.0 mg/L. A close association was observed between a higher CRP level (CRP≥5.0 mg/L) and clinical stage (χ2 trend test: P = 0.005), clinical nodal status (χ2 trend test: P = 0.003), and tumor differentiation (χ2trend test: P = 0.014) (Table 2). A close association was also observed between a higher SCC-Ag level (SCC-Ag ≥2.0 ng/ml) and clinical stage (χ2 trend test: P = 0.001), clinical tumor status (χ2 trend test: P<0.001), and clinical nodal status (χ2 trend test: P = 0.001). Furthermore, higher SCC-Ag levels were often accompanied by higher serum CRP levels (χ2 test: P = 0.006).
When the patients were divided into four groups according to individual pre-treatment levels of SCC-Ag and CRP, a close association was observed between higher levels of SCC-Ag (≥2.0 ng/ml) and CRP (≥5.0 mg/L) and clinical stage (χ2 trend test: P<0.001), clinical tumor status (χ2 trend test: P<0.001), and clinical nodal status (χ2 trend test: P<0.001) (Table 3).
We next compared the association between CRP level, SCC-Ag level, SUVtumor-max and SUVnodal-max and found that the levels of CRP and SCC-Ag were not associated with SUVtumor-max (linear regression, P = 0.070 and P = 0.425, respectively). However, a significant association between CRP level, SCC-Ag level and SUVnodal-max (linear regression, P = 0.023 and P = 0.043, respectively) was observed.
Similar results were also found in the analysis of SUV. When the patients were divided into 4 groups according to pre-treatment SUVtumor-max and SUVnodal-max values obtained by FDG-PET, a close association was observed between higher values of SUVtumor-max (≥8.6) and SUVnodal-max (≥5.7) and clinical stage (χ2 trend test: P<0.001), clinical tumor status (χ2 trend test: P<0.001), and nodal status (χ2 trend test: P<0.001). The associations between the 4 patient groups according to SUVtumor-max and SUVnodal-max and according to the pre-treatment levels of SCC-Ag and CRP were also analyzed and found to be significant (P = 0.019) (χ2 trend test: Table 4).
Combined CRP and SCC-Ag Levels and their Relationships with Prognosis
Regarding the clinicopathological factors influencing patient survival, only tumor status (P = 0.020) and CRP (P = 0.010) had significant influences on overall survival (OS) in the univariate analysis. We combined the CRP and SCC-Ag levels as a variable value for the analysis of prognosis, for which the patients were divided into four groups. For the analysis of all 103 patients in the study, the OS with higher SCC-Ag and higher CRP levels (n = 27) was significantly different to that with non-elevated levels of SCC-Ag and CRP (n = 76) (log-rank test, P = 0.016), although the disease-free survival (DFS) of patients was not significantly different between groups (log-rank test, P = 0.747).
The Clinical Effects and Molecular Mechanism of SCC-Ag in PLC
The squamous cell carcinoma antigen (SCC-Ag) is a tumor-associated protein that was first isolated from SCC tissues of the uterine cervix.  Importantly, this antigen may promote tumorigenesis via a number of different mechanisms. For example, transduction of SCC-Ag into tumor cells has been shown to inhibit apoptosis and promote tumor cell survival,  and SCC-Ag can increase cell migration without affecting cell growth, which results in tumor invasion and metastasis. ,  The pro-invasive characteristics of SCC-Ag have also demonstrated positive associations between serum SCC-Ag level and tumor progression, lymph node metastasis and tumor stage. , , , , , ,  The present study also confirmed the positive relationship between SCC-Ag level and clinical stage, clinical tumor status, and clinical nodal status (P = 0.001, P<0.001, P = 0.001, respectively) (Table 2). In response to stimulation by epidermal growth factor, intracellular SCC-Ag has been shown to translocate to the plasma membrane, and exogenously expressed SCC-Ag then serves to increase cell migration without affecting cell growth.  Thus, SCC-Ag may play a role in tumor invasion and metastasis.
The Clinical Effects and Molecular Mechanism of CRP in PLC
Serum CRP level is a sensitive marker of inflammation that is elevated in response to tissue damage or infection and has been shown to be a prognostic factor in OSCC. , ,  This acute-phase reactive protein is produced primarily in the liver, and its expression is up-regulated by pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF).  CRP level is elevated in chronic inflammatory environments, which may lead to excessive cell proliferation and subsequent accumulation of DNA damage. The host immune system responds to tumor growth via elevated levels of inflammatory cytokines, which may further increase CRP levels. , .
Reports from the study of oral cavity SCC have suggested a relationship between CRP level and poor outcomes, pathological tumor status, nodal status and lymph node ECS. , , ,  However, few studies have investigated the role of CRP in PLC. (Table S1) , , , ,  The current study, which includes the largest number of patients, demonstrated that an elevated CRP level was associated with clinical tumor status (P = 0.005), clinical nodal status (P = 0.003) and differentiation of tumor cells (P = 0.014) in PLC, which is similar to previous findings with OSCC. .
The Correlation between CRP, SCC-Ag and the SUVmax of FDG-PET
FDG-PET has been increasingly applied in head and neck cancer patients for staging and for the study of tumor aggressiveness through the measurement of SUV. , , , ,  Furthermore, studies have demonstrated that the SUVmax values of either the primary tumor or the neck lymph nodes are independent prognostic factors in cases of OSCC. ,  Elevated levels of CRP and SCC-Ag were associated with SUVnodal-max (P = 0.017, P = 0.027, respectively), and the correlation between CRP and SCC-Ag levels were also significant in the current study (P = 0.006).
The combined measurement of SCC-Ag and CRP revealed a more significant correlation with clinical status than either SCC-Ag or CRP when used alone. The patient subgroup with positive levels of both SCC-Ag and CRP demonstrated a profoundly significant association with clinical stage (P<0.001), clinical tumor status (P<0.001) and nodal status (P<0.001) compared to other patient groups (Table 3). The combined value of SCC-Ag and CRP was significantly correlated with the combined value of SUVtumor-max and SUVnodal-max (P = 0.019), which indicates that the preoperative levels of SCC-Ag and CRP together represent a valuable marker for the evaluation of tumor aggressiveness in PLC.
When tumor cells proliferate rapidly, there is an increase in glucose consumption, which be observed as an increase in glucose uptake on a FDG-PET scan. The destruction of nearby tissue and lymph node metastasis is generally accompanied by tissue inflammation, and the infiltration of inflammatory cells and the production of cytokines, especially IL-6, increase the CRP level in the serum. In addition, T-lymphocytes located at the periphery of tumors serve to increase the production of SCC-Ag,  which causes accelerated tumor growth to be associated with elevated levels of SCC-Ag and CRP. Moreover, these changes were each reflected as an increase in the SUVmax via PET scan. According to our analyses, the combined use of these two serum markers represents an easy method to evaluate the aggressiveness of PLC tumors. Concerning the FDG-PET analysis, the SUVmax of the primary tumor mass has previously been shown to be related to differences in cellular grade and tumor aggressiveness. , .
We further analyzed the significance of SCC-Ag and CRP in PLC and found no significant correlation between SCC-Ag level, DFS and OS in a univariate analysis (P = 0.675 and P = 0.313, respectively) (Table 5). In addition, there was significant correlation between CRP level and OS (P = 0.010) but not DFS (P = 0.368) in the univariate analysis(Table 5). The combined value of SCC-Ag and CRP demonstrated a non-significant correlation with DFS (log-rank test, P = 0.747, Table 5) but a significant association with OS (log-rank test, P = 0.016, Table 5). The role of SCC-Ag in human cancers has been demonstrated in a number of clinical studies, ,  which suggests that the serum SCC-Ag level is useful for evaluating responses to radiotherapy and chemotherapy and for predicting early recurrence. This may be related to the molecular role of SCC-Ag in protecting against tumor cell apoptosis. The elevation of CRP arises from the host immune responses to tumor growth with elevated inflammatory cytokines.  In patients who received chemo-radiation therapy, CRP is not only an indicator of the host response in the tumor microenvironment but also a reflection of tumor cell killing and local tissue damage  either by host or by treatment. From this study, when both SCC-Ag and CRP levels were elevated, the patients could be at risk of worse survival outcome. Further confirmatory studies with a larger number of patients and a longer follow-up period are required due to the limited sample size of the present study. In addition, the radiation responsiveness at different sub-sites should be stratified in a larger number of patients.
The present study demonstrated that the combined measurement of SCC-Ag and CRP levels served as a marker of clinical status in PLC and may represent a biomarker capable of predicting prognosis. However, further work is required to elucidate the precise molecular mechanisms for this observed interaction between SCC-Ag and CRP in PLC. As measurements of the levels of SCC-Ag and CRP can be performed quickly, inexpensively and repeatably in a clinical setting, we believe that the levels of SCC-Ag and CRP, as well as the combination of these two factors, could serve as relevant biomarkers of tumor aggressiveness prior to treatment in patients with PLC.
Literature discussing the role of C-reactive protein (CRP) in oropharyngeal cancer.
We thank Dr. Chris Wallace for his critical opinions and editing of this manuscript.
Data acquisition: HMW KHF CYL TCY. Clinical studies: HSF HMW KHF CYL. Conceived and designed the experiments: HHC SFH. Performed the experiments: HHC SFH. Analyzed the data: SFH CTL CJK IHC. Contributed reagents/materials/analysis tools: SFH CTL. Wrote the paper: HHC SFH.
- 1. Cancer registry annual report in Taiwan Area. Department of Health, the Executive Yuan, Taiwan, R.O. C: 2009.
- 2. Chen PH, Shieh TY, Ho PS, Tsai CC, Yang YH, et al. (2007) Prognostic factors associated with the survival of oral and pharyngeal carcinoma in Taiwan. BMC Cancer 7: 101.
- 3. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, et al. (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100: 261–269.
- 4. Lin WH, Chen IH, Wei FC, Huang JJ, Kang CJ, et al. (2011) Clinical significance of preoperative squamous cell carcinoma antigen in oral-cavity squamous cell carcinoma. Laryngoscope 121: 971–977.
- 5. Allin KH, Bojesen SE, Nordestgaard BG (2009) Baseline C-reactive protein is associated with incident cancer and survival in patients with cancer. J Clin Oncol 27: 2217–2224.
- 6. Mahmoud FA, Rivera NI (2002) The role of C-reactive protein as a prognostic indicator in advanced cancer. Curr Oncol Rep 4: 250–255.
- 7. McMillan DC, Elahi MM, Sattar N, Angerson WJ, Johnstone J, et al. (2001) Measurement of the systemic inflammatory response predicts cancer-specific and non-cancer survival in patients with cancer. Nutr Cancer 41: 64–69.
- 8. Chen HH, Chen IH, Liao CT, Wei FC, Lee LY, et al. (2011) Preoperative circulating C-reactive protein levels predict pathological aggressiveness in oral squamous cell carcinoma: a retrospective clinical study. Clin Otolaryngol 36: 147–153.
- 9. Huang SF, Wei FC, Liao CT, Wang HM, Lin CY, et al.. (2012) Risk Stratification in Oral Cavity Squamous Cell Carcinoma by Preoperative CRP and SCC Antigen Levels. Ann Surg Oncol.
- 10. Zhang B, Li X, Lu X (2010) Standardized uptake value is of prognostic value for outcome in head and neck squamous cell carcinoma. Acta Otolaryngol 130: 756–762.
- 11. Vansteenkiste JF, Stroobants SG, Dupont PJ, De Leyn PR, Verbeken EK, et al. (1999) Prognostic importance of the standardized uptake value on (18)F-fluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: An analysis of 125 cases. Leuven Lung Cancer Group. J Clin Oncol 17: 3201–3206.
- 12. Gambhir SS (2002) Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2: 683–693.
- 13. Nakamura K, Okumura Y, Kodama J, Hongo A, Kanazawa S, et al. (2010) The predictive value of measurement of SUVmax and SCC-antigen in patients with pretreatment of primary squamous cell carcinoma of cervix. Gynecol Oncol 119: 81–86.
- 14. Schwarz JK, Siegel BA, Dehdashti F, Grigsby PW (2007) Association of posttherapy positron emission tomography with tumor response and survival in cervical carcinoma. JAMA 298: 2289–2295.
- 15. Shimoda W, Hayashi M, Murakami K, Oyama T, Sunagawa M (2007) The relationship between FDG uptake in PET scans and biological behavior in breast cancer. Breast Cancer 14: 260–268.
- 16. Pectasides D, Bafaloucos D, Antoniou F, Gogou L, Economides N, et al. (1996) TPA, TATI, CEA, AFP, beta-HCG, PSA, SCC, and CA 19–9 for monitoring transitional cell carcinoma of the bladder. Am J Clin Oncol 19: 271–277.
- 17. Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17: 1471–1474.
- 18. Wang HM, Wang CS, Chen JS, Chen IH, Liao CT, et al. (2002) Cisplatin, tegafur, and leucovorin: a moderately effective and minimally toxic outpatient neoadjuvant chemotherapy for locally advanced squamous cell carcinoma of the head and neck. Cancer 94: 2989–2995.
- 19. Huang SF, Kang CJ, Lin CY, Fan KH, Yen TC, et al. (2008) Neck treatment of patients with early stage oral tongue cancer: comparison between observation, supraomohyoid dissection, and extended dissection. Cancer 112: 1066–1075.
- 20. Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, et al. (2008) Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol 15: 915–922.
- 21. Oka M, Yamamoto K, Takahashi M, Hakozaki M, Abe T, et al. (1996) Relationship between serum levels of interleukin 6, various disease parameters, and malnutrition in patients with esophageal squamous cell carcinoma. Cancer Research 56: 2776–2780.
- 22. Liao CT, Wang HM, Chang JT, Lin CY, Ng SH, et al. (2010) Influence of pathological nodal status and maximal standardized uptake value of the primary tumor and regional lymph nodes on treatment plans in patients with advanced oral cavity squamous cell carcinoma. Int J Radiat Oncol Biol Phys 77: 421–429.
- 23. Kidd EA, Siegel BA, Dehdashti F, Grigsby PW (2007) The standardized uptake value for F-18 fluorodeoxyglucose is a sensitive predictive biomarker for cervical cancer treatment response and survival. Cancer 110: 1738–1744.
- 24. Kato H, Torigoe T (1977) Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer 40: 1621–1628.
- 25. Takeda A, Kajiya A, Iwasawa A, Nakamura Y, Hibino T (2002) Aberrant expression of serpin squamous cell carcinoma antigen 2 in human tumor tissues and cell lines: evidence of protection from tumor necrosis factor-mediated apoptosis. Biol Chem 383: 1231–1236.
- 26. Sueoka K, Nawata S, Nakagawa T, Murakami A, Takeda O, et al. (2005) Tumor-associated serpin, squamous cell carcinoma antigen stimulates matrix metalloproteinase-9 production in cervical squamous cell carcinoma cell lines. Int J Oncol 27: 1345–1353.
- 27. Kimura Y, Fujieda S, Takabayashi T, Tanaka T, Sugimoto C, et al. (2000) Conventional tumor markers are prognostic indicators in patients with head and neck squamous cell carcinoma. Cancer Lett 155: 163–168.
- 28. Molina R, Torres MD, Moragas M, Perez-Villa J, Filella X, et al. (1996) Prognostic significance of SCC antigen in the serum of patients with head and neck cancer. Tumour Biol 17: 81–89.
- 29. Krimmel M, Hoffmann J, Krimmel C, Cornelius CP, Schwenzer N (1998) Relevance of SCC-Ag, CEA, CA 19.9 and CA 125 for diagnosis and follow-up in oral cancer. J Craniomaxillofac Surg 26: 243–248.
- 30. Lara PC, Cuyas JM (1995) The role of squamous cell carcinoma antigen in the management of laryngeal and hypopharyngeal cancer. Cancer 76: 758–764.
- 31. Yasumatsu R, Nakashima T, Azuma K, Hirakawa N, Kuratomi Y, et al. (2001) SCCA1 expression in T-lymphocytes peripheral to cancer cells is associated with the elevation of serum SCC antigen in squamous cell carcinoma of the tongue. Cancer Lett 167: 205–213.
- 32. Lachowicz MA, Hassmann-Poznanska E, Kozlowski MD, Rzewnicki I (1999) Squamous cell carcinoma antigen in patients with cancer of the larynx. Clin Otolaryngol Allied Sci 24: 270–273.
- 33. Emoto T, Nakamura K (2008) EGF stimulates Cdc42-dependent translocation of SCC antigen to the plasma membrane. Biochem Biophys Res Commun 370: 495–498.
- 34. Il’yasova D, Colbert LH, Harris TB, Newman AB, Bauer DC, et al. (2005) Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort. Cancer Epidemiol Biomarkers Prev 14: 2413–2418.
- 35. Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ (2004) C-reactive protein and the risk of incident colorectal cancer. JAMA 291: 585–590.
- 36. Baron JA (2003) Epidemiology of non-steroidal anti-inflammatory drugs and cancer. Prog Exp Tumor Res 37: 1–24.
- 37. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420: 860–867.
- 38. Gallo O, Gori AM, Attanasio M, Martini F, Giusti B, et al. (1995) Interleukin-6 and acute-phase proteins in head and neck cancer. Eur Arch Otorhinolaryngol 252: 159–162.
- 39. Jablonska E, Piotrowski L, Grabowska Z (1997) Serum Levels of IL-1b, IL-6, TNF-a, sTNF-RI and CRP in Patients with Oral Cavity Cancer. Pathol Oncol Res 3: 126–129.
- 40. Khandavilli SD, Ceallaigh PO, Lloyd CJ, Whitaker R (2009) Serum C-reactive protein as a prognostic indicator in patients with oral squamous cell carcinoma. Oral Oncol 45: 912–914.
- 41. Tartour E, Deneux L, Mosseri V, Jaulerry C, Brunin F, et al. (1997) Soluble interleukin-2 receptor serum level as a predictor of locoregional control and survival for patients with head and neck carcinoma: results of a multivariate prospective study. Cancer 79: 1401–1408.
- 42. Kulpa J, Stasik Z, Skolyszewski J, Wojcik E, Rychlik U, et al. (2004) Predictive value of SCC-Ag, CYFRA 21–1 and selected acute phase proteins in radiotherapy of pharyngeal and laryngeal cancer. A preliminary report. Neoplasma 51: 103–109.
- 43. Dhankhar R, Dahiya K, Sharma TK, Ghalaut VS, Atri R, et al. (2011) Diagnostic significance of adenosine deaminase, uric acid and C-reactive protein levels in patients of head and neck carcinoma. Clin Lab 57: 795–798.
- 44. Zeng YC, Xue M, Chi F, Xu ZG, Fan GL, et al. (2012) C-reactive protein level predicts prognosis in patients with locoregionally advanced laryngeal carcinoma treated with chemoradiotherapy. Tumour Biol 33: 891–895.
- 45. Ng SH, Yen TC, Liao CT, Chang JT, Chan SC, et al. (2005) 18F-FDG PET and CT/MRI in oral cavity squamous cell carcinoma: a prospective study of 124 patients with histologic correlation. J Nucl Med 46: 1136–1143.
- 46. Schoder H, Carlson DL, Kraus DH, Stambuk HE, Gonen M, et al. (2006) 18F-FDG PET/CT for detecting nodal metastases in patients with oral cancer staged N0 by clinical examination and CT/MRI. J Nucl Med 47: 755–762.
- 47. Wensing BM, Vogel WV, Marres HA, Merkx MA, Postema EJ, et al. (2006) FDG-PET in the clinically negative neck in oral squamous cell carcinoma. Laryngoscope 116: 809–813.
- 48. Ng SH, Yen TC, Chang JT, Chan SC, Ko SF, et al. (2006) Prospective study of [18F]fluorodeoxyglucose positron emission tomography and computed tomography and magnetic resonance imaging in oral cavity squamous cell carcinoma with palpably negative neck. J Clin Oncol 24: 4371–4376.
- 49. Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, et al. (2009) Preoperative [18F]fluorodeoxyglucose positron emission tomography standardized uptake value of neck lymph nodes predicts neck cancer control and survival rates in patients with oral cavity squamous cell carcinoma and pathologically positive lymph nodes. Int J Radiat Oncol Biol Phys 74: 1054–1061.
- 50. Allal AS, Slosman DO, Kebdani T, Allaoua M, Lehmann W, et al. (2004) Prediction of outcome in head-and-neck cancer patients using the standardized uptake value of 2-[18F]fluoro-2-deoxy-D-glucose. Int J Radiat Oncol Biol Phys 59: 1295–1300.
- 51. Kim SY, Roh JL, Kim MR, Kim JS, Choi SH, et al. (2007) Use of 18F-FDG PET for primary treatment strategy in patients with squamous cell carcinoma of the oropharynx. J Nucl Med 48: 752–757.
- 52. Ngan HY, Chan SY, Wong LC, Choy DT, Ma HK (1990) Serum squamous cell carcinoma antigen in the monitoring of radiotherapy treatment response in carcinoma of the cervix. Gynecol Oncol 37: 260–263.
- 53. Scambia G, Panici PB, Baiocchi G, Amoroso M, Foti E, et al. (1991) The value of squamous cell carcinoma antigen in patients with locally advanced cervical cancer undergoing neoadjuvant chemotherapy. Am J Obstet Gynecol 164: 631–636.
- 54. McMillan DC, Canna K, McArdle CS (2003) Systemic inflammatory response predicts survival following curative resection of colorectal cancer. Br J Surg 90: 215–219.